Novel complex cyclic compound

Abstract

The present invention relates to a compound of formula 1 ~R 4 , m, n and p are as described herein; TIFF2023510971000176.tif5284 and pharmaceutically acceptable salts thereof. Pharmaceutical compositions containing the compounds, methods for making the compounds, and methods for using the compounds as medicines, particularly as antibiotics for the treatment or prevention of bacterial infections and diseases resulting therefrom, are also provided.

Description

Technical Field

[0001] Field of the Invention The present invention relates to novel heterocyclic compounds exhibiting antibacterial properties. The present invention also relates to methods of using compounds for the treatment or prevention of bacterial infections and diseases caused thereby, particularly for the treatment or prevention of infections and diseases caused by Acinetobacter baumannii.

Background Art

[0002] Background of the Invention Acinetobacter baumannii is a Gram-negative, aerobic, and non-fermentative bacterium that has been recognized as a novel pathogen with extremely limited treatment options in recent decades.

[0003] Acinetobacter baumannii is regarded as a serious threat by the US Centers for Disease Control and Prevention and currently causes the majority of hospital-acquired infections and belongs to the so-called "ESKAPE" pathogens (Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter species and Escherichia coli) that can effectively "escape" the activity of antibacterial agents.

[0004] Acinetobacter baumannii can be selected for resistance to all known antibacterial drugs by widespread use of antibiotics and most frequently occurs in intensive care units and surgical wards where it can cause infections such as bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections.

[0005] Acinetobacter baumannii has an excellent ability to upregulate and acquire resistance determinants and exhibits environmental persistence that allows its survival and spread in the hospital environment. As a result, the organism frequently causes infections and becomes a healthcare-related pathogen specific to that environment.

[0006] For most, if not all, available therapeutic options, the increasing antibiotic resistance has made the treatment of multi-drug resistant (MDR) A. baumannii infections, particularly those caused by carbapenem-resistant A. baumannii, extremely difficult or even impossible, leading to increased morbidity and length of stay in the intensive care unit, as well as high mortality.

[0007] According to the Antimicrobial Availability Task Force (AATF) of the Infectious Diseases Society of America (IDSA), Acinetobacter baumannii has been and remains a "classic example of the mismatch between unmet medical needs and the current antibacterial research and development pipeline." Thus, there is a high demand and need to identify compounds suitable for the treatment of diseases and infections caused by Acinetobacter baumannii. The present invention provides novel compounds that are active against both susceptible and resistant strains of Acinetobacter baumannii.

Summary of the Invention

[0008] Summary of the Invention In a first aspect, the present invention provides a compound of formula (I)

Chemical Formula

[0009] In one aspect, the present invention provides a method for manufacturing a compound of formula (I) described herein or a combination thereof, which is the method described in any one of Schemes 1-5.

[0010] In a further aspect, the present invention provides a compound of formula (I) described herein when manufactured according to the method described herein.

[0011] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutic active substance.

[0012] In a further aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

[0013] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0014] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and diseases resulting therefrom.

[0015] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases resulting therefrom.

[0016] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Enterobacter species or Escherichia coli or combinations thereof and diseases resulting therefrom.

[0017] In a further aspect, the present invention provides a method for treating or preventing an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and a resulting disease, comprising administering to a mammal a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0018] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

[0019] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for treating or preventing an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and a resulting disease.

[0020] In a further aspect, the present invention provides the use of a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for treating or preventing an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and a resulting disease.

Mode for Carrying Out the Invention

[0021] Detailed Description of the Invention Definitions It should be understood that any feature, integer, characteristic, compound, chemical moiety, or group described in connection with a particular aspect, embodiment, or example of the invention is applicable to any other aspect, embodiment, or example described herein, except where inconsistent therewith. All features disclosed herein (including any accompanying claims, abstract, and drawings), and / or all steps of any method or process so disclosed, may be combined in any combination, except combinations in which at least some of such features and / or steps are mutually exclusive. The invention is not limited to the details of any of the foregoing embodiments. The invention extends to any novel or any novel combination of features disclosed herein (including any accompanying claims, abstract, and drawings), or any novel or any novel combination of steps of any method or process so disclosed.

[0022] The term "alkyl" refers to a monovalent or polyvalent, e.g., monovalent or divalent, straight-chain or branched saturated hydrocarbon group ("C1-C6-alkyl") of 1 to 6 carbon atoms, e.g., 1, 2, 3, 4, 5, or 6 carbon atoms. In some embodiments, an alkyl group contains 1 to 3 carbon atoms, e.g., 1, 2, or 3 carbon atoms. Some non-limiting examples of alkyl include methyl, ethyl, propyl, 2-propyl (isopropyl), n-butyl, iso-butyl, sec-butyl, tert-butyl, and 2,2-dimethylpropyl. A particularly preferred, but non-limiting, example of alkyl is methyl.

[0023] The term "alkynyl" means a monovalent linear or branched hydrocarbon group of 2 to 6 carbon atoms having at least one triple bond ("C2-C6-alkynyl"). In certain embodiments, the alkynyl has 2 to 4 carbon atoms having at least one triple bond. Examples of alkynyl include ethynyl, propynyl, n-butynyl, or isobutynyl. A preferred alkynyl is propynyl.

[0024] The term "alkoxy" refers to an alkyl group as defined above, which is bonded to the parent molecular moiety via an oxygen atom. Unless otherwise specified, an alkoxy group is a "C1-C6-alkoxy" containing 1 to 6 carbon atoms. In some preferred embodiments, the alkoxy group contains 1 to 4 carbon atoms. In still other embodiments, the alkoxy group contains 1 to 3 carbon atoms. Some non-limiting examples of alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, and tert-butoxy. A particularly preferred but non-limiting example of alkoxy is methoxy.

[0025] The term "halogen" or "halo" refers to fluoro (F), chloro (Cl), bromo (Br), or iodo (I). Preferably, the term "halogen" or "halo" refers to fluoro (F), chloro (Cl), or bromo (Br). Particularly preferred but non-limiting examples of "halogen" or "halo" are fluoro (F) and chloro (Cl).

[0026] As used herein, the term "cycloalkyl" refers to a saturated or partially unsaturated, monocyclic or bicyclic hydrocarbon group having 3 to 10 ring carbon atoms ("C3-C 10 -cycloalkyl"). In some preferred embodiments, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 8 ring carbon atoms. "Bicyclic cycloalkyl" refers to a cycloalkyl moiety consisting of two saturated carbon rings having 2 common carbon atoms, i.e., the bridge separating the two rings is either a single bond or a chain of 1 or 2 ring atoms, or a spiro ring moiety, i.e., a cycloalkyl moiety in which the two rings are joined via 1 common ring atom. Preferably, the cycloalkyl group is a saturated monocyclic hydrocarbon group having 3 to 6 ring carbon atoms, for example, 3, 4, 5, or 6 carbon atoms. Some non-limiting examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and spiro[2.3]hexan-5-yl.

[0027] The term "aminoalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by an amino group. Preferably, "aminoalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by an amino group. Preferred but non-limiting examples of aminoalkoxy are aminomethoxy and 1-aminoethoxy.

[0028] The term "aminoalkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is substituted by an aminoalkoxy group. Preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are substituted by an aminoalkoxy group. Most preferably, "aminoalkoxyalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is substituted by an aminoalkoxy group.

[0029] The term "heterocyclyl" refers to a saturated or partially unsaturated monocyclic or bicyclic, preferably monocyclic ring system of 3 to 10 ring atoms, preferably 3 to 8 ring atoms, wherein 1, 2, or 3 of said ring atoms are heteroatoms selected from N, O, and S, and the remaining ring atoms are carbon. Preferably, 1 to 2 of said ring atoms are selected from N and O, and the remaining ring atoms are carbon. "Bicyclic heterocyclyl" refers to a heterocyclic moiety consisting of two rings having 2 common ring atoms, i.e., the bridge separating the two rings is either a single bond or a chain of 1 or 2 ring atoms, or a spiro ring moiety, i.e., a heterocyclic moiety in which the two rings are joined via 1 common ring atom. Some non-limiting examples of heterocyclyl groups include azetidin-3-yl, azetidin-2-yl, oxetan-3-yl, oxetan-2-yl, piperidyl, piperazinyl, pyrrolidinyl, 2-oxopyrrolidin-1-yl, 2-oxopyrrolidin-3-yl, 5-oxopyrrolidin-2-yl, 5-oxopyrrolidin-3-yl, 2-oxo-1-piperidyl, 2-oxo-3-piperidyl, 2-oxo-4-piperidyl, 6-oxo-2-piperidyl, 6-oxo-3-piperidyl, 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-piperidinyl, morpholino, morpholin-2-yl, morpholin-3-yl, pyrrolidinyl (e.g., pyrrolidin-3-yl), 3-azabicyclo[3.1.0]hexan-6-yl, 2,5-diazabicycl[2.2.1]heptan-2-yl, 2-azaspiro[3.3]heptan-2-yl; 2,6-diazaspiro[3.3]heptan-2-yl; and 2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrol-5-yl.

[0030] The term "aryl" refers to a monocyclic, bicyclic, or tricyclic carbocyclic ring system having a total of 6 to 10 ring members ("C6-C 10 -aryl"), wherein at least one ring of this system is aromatic. A particularly preferred, but non-limiting, example of aryl is phenyl.

[0031] The term "heteroaryl" refers to a monovalent or polyvalent, monocyclic or bicyclic, preferably bicyclic ring system having a total of 5 to 14 ring members, preferably 5 to 12 ring members, more preferably 5 to 10 ring members, wherein at least one ring of the system is aromatic and at least one ring of the system contains one or more heteroatoms. Preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1, 2, 3 or 4 heteroatoms independently selected from O, S, and N. Most preferably, "heteroaryl" refers to a 5- to 10-membered heteroaryl containing 1 to 2 heteroatoms independently selected from O and N. Some non-limiting examples of heteroaryl include 2-pyridyl, 3-pyridyl, 4-pyridyl, pyrimidin-2-yl, pyrimidin-4-yl, pyrimidin-5-yl, pyrimidin-6-yl, indol-1-yl, 1H-indol-2-yl, 1H-indol-3-yl, 1H-indol-4-yl, 1H-indol-5-yl, 1H-indol-6-yl, 1H-indol-7-yl, 1,2-benzoxazol-3-yl, 1,2-benzoxazol-4-yl, 1,2-benzoxazol-5-yl, 1,2-benzoxazol-6-yl, 1,2-benzoxazol-7-yl, 1H-indazol-3-yl, 1H-indazol-4-yl, 1H-indazol-5-yl, 1H-indazol-6-yl, 1H-indazol-7-yl, pyrazol-1-yl, 1H-pyrazol-3-yl, 1H-pyrazol-4-yl, 1H-pyrazol-5-yl, imidazol-1-yl, 1H-imidazol-2-yl, 1H-imidazol-4-yl, 1H-imidazol-5-yl, oxazol-2-yl, oxazol-4-yl, oxazol-5-yl, thiazol-4-yl, and 1,2,4-oxadiazol-3-yl. Most preferably, "heteroaryl" refers to pyridyl and pyrimidinyl.

[0032] The term "heteroaryloxy" refers to a heteroaryl group as defined above attached to the parent molecular moiety via an oxygen atom.

[0033] The term "hydroxy" refers to an -OH group.

[0034] The term "amino" refers to the -NH2 group.

[0035] The term "cyano" refers to the -CN (nitrile) group.

[0036] The term "oxo" refers to a double-bonded oxygen (=O).

[0037] The term "carbamoyl" refers to the -C(O)NH2 group.

[0038] The term "alkylimido-yl" refers to the group [Chemical formula] as shown.

[0039] The term "carboxy" refers to the -C(O)OH group (i.e., the carboxy cyclic acid moiety).

[0040] The term "carbonyl" refers to a carbon radical having two of the four covalent bonds shared with an oxygen atom (C=O).

[0041] The term "haloalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkyl" refers to an alkyl group in which one, two, or three hydrogen atoms of the alkyl group are replaced by a halogen atom, most preferably fluorine. Non-limiting examples of haloalkyl are fluoromethyl, difluoromethyl, trifluoromethyl, trifluoroethyl, 2-fluoroethyl, and 2,2-difluoroethyl. A particularly preferred but non-limiting example of haloalkoxy is trifluoromethyl.

[0042] The term "cyanoalkyl" refers to an alkyl group in which at least one hydrogen atom of the alkyl group is replaced by a cyano group. Preferably, "cyanoalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group are replaced by cyano groups. Most preferably, "cyanoalkyl" refers to an alkyl group in which one hydrogen atom of the alkyl group is replaced by a cyano group.

[0043] The term "haloalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a halogen atom, preferably fluorine. Preferably, "haloalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by a halogen atom, most preferably fluorine. Particularly preferred but non-limiting examples of haloalkoxy are fluoromethoxy (FCH2O-), difluoromethoxy (F2CHO-), and trifluoromethoxy (F3CO-).

[0044] The term "cyanoalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a cyano group. Preferably, "cyanoalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by cyano groups. Most preferably, "cyanoalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a cyano group.

[0045] The term "carbamoylalkoxy" refers to an alkoxy group in which at least one hydrogen atom of the alkoxy group is replaced by a carbamoyl group. Preferably, "carbamoylalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by carbamoyl groups. Most preferably, "carbamoylalkoxy" refers to an alkoxy group in which one hydrogen atom of the alkoxy group is replaced by a carbamoyl group.

[0046] The term "alkoxyalkoxy" refers to an alkoxy group in which at least one of the hydrogen atoms of the alkoxy group is replaced by an alkoxy group, preferably a methoxy group. Preferably, "alkoxyalkoxy" refers to an alkoxy group in which one, two or three hydrogen atoms of the alkoxy group are replaced by an alkoxy group, most preferably a methoxy group. A particularly preferred but non-limiting example of alkoxyalkoxy is 2-methoxyethoxy.

[0047] The term "hydroxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a hydroxy group. Preferably, "hydroxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by a hydroxy group. Preferred but non-limiting examples of hydroxyalkyl are hydroxymethyl, hydroxyethyl (e.g., 2-hydroxyethyl), and 3-hydroxy-3-methyl-butyl.

[0048] The term "aminoalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by an amino group. Preferably, "aminoalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by an amino group. Preferred but non-limiting examples of aminoalkyl are aminomethyl, aminoethyl (e.g., 2-aminoethyl) and 3-amino-3-methyl-butyl.

[0049] The term "carboxyalkyl" refers to an alkyl group in which at least one of the hydrogen atoms of the alkyl group is replaced by a carboxy group. Preferably, "carboxyalkyl" refers to an alkyl group in which one, two or three hydrogen atoms of the alkyl group, most preferably one hydrogen atom, are replaced by a carboxy group. Preferred but non-limiting examples of carboxyalkyl are carboxymethyl, carboxyethyl (e.g., 2-carboxyethyl), and 3-carboxy-3-methyl-butyl.

[0050] The term "pharmaceutically acceptable salt" refers to salts which retain the biological effectiveness and properties of the free base or free acid and which are not biologically or otherwise undesirable. The salts are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, especially hydrochloric acid, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, lactic acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, N-acetylcysteine and the like. In addition, these salts can be prepared by adding an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, sodium, potassium, lithium, ammonium, calcium and magnesium salts. Salts derived from organic bases include salts of primary, secondary and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, lysine, arginine, N-ethylpiperidine, piperidine, polyimine resins and the like. Specific pharmaceutically acceptable salts of the compound of formula (I) are hydrochloride, fumarate, lactate (especially derived from L-(+)-lactic acid), tartrate (especially derived from L-(+)-tartaric acid) and trifluoroacetate.

[0051] The compound of formula (I) can contain several asymmetric centers and can exist as optically pure enantiomers, mixtures of enantiomers such as racemates etc., optically pure diastereoisomers, mixtures of diastereoisomers, diastereoisomeric racemates or mixtures of diastereoisomeric racemates.

[0052] According to the Cahn-Ingold-Prelog rules, an asymmetric carbon atom can be of the "R" or "S" configuration.

[0053] As used herein, the term "treatment" includes: (1) suppressing a symptom, disorder or condition (e.g., in the case of maintenance treatment, stopping, reducing or delaying the onset, recurrence of at least one clinical symptom or asymptomatic disease); and / or (2) alleviating a condition (i.e., causing regression of a symptom, disorder or condition, or at least one of its clinical or asymptomatic manifestations). The benefit to the patient to be treated is either statistically significant or at least recognizable to the patient or physician. However, it will be understood that when a drug is administered to a patient to treat a disease, the outcome need not necessarily be an effective treatment.

[0054] As used herein, the term "prevention" includes, in mammals, particularly in humans who are affected by or are susceptible to a condition, disorder or situation but have not yet experienced or manifested the clinical or asymptomatic manifestations of that condition, disorder or situation, preventing or delaying the appearance of the clinical manifestations of the condition, disorder or situation.

[0055] As used herein, the term "mammal" includes both humans and non-humans, including but not limited to humans, non-human primates, dogs, cats, rats, cows, horses, and pigs. In a particularly preferred embodiment, the term "mammal" refers to a human.

[0056] The term "nosocomial infection" refers to healthcare-associated infections (HAI), which are infections acquired in a hospital or other healthcare facility. To emphasize both hospital and non-hospital settings, it may also be called healthcare-associated infection (HAI or HCAI). Such infections can be acquired in hospitals, nursing homes, rehabilitation facilities, outpatient clinics, or other clinical settings.

[0057] The compounds of the present invention In a first aspect, the present invention provides a compound of formula (I):

Chemical formula

[0058] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein m is 1.

[0059] In one embodiment, the present invention provides R 1 is selected from amino, amino-C1-C6-alkoxy-,

Chemical formula

[0060] In a preferred embodiment, the present invention relates to R 1 which is a group

Chemical formula

[0061] In one embodiment, the present invention relates to L 1 which is selected from -CH2O-, -(CH2) s C(O)-, -CH2NHC(O)-, -CH2C(O)NH-, -CH2-, -NHC(O)-, -S(O)2-, -S(O)2NH-, -C(O)NH(CH2)2-, and -NH-NHC(O)-, and there is provided a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0062] In a preferred embodiment, the present invention relates to L 1 which is selected from carbonyl, -CH-2C(O)-, -CH2-NH-C(O)- and -NHC(O)-, and there is provided a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0063] In a preferred embodiment, the present invention relates to L 2 which is selected from a covalent bond, carbonyl, -S(O)2-, -NHC(O)-, -C(O)NH-, and -S(O)2NH-, and there is provided a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof.

[0064] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 2.

[0065] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein q is 0 or 1.

[0066] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 0, 1 or 4.

[0067] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from 3- to 14-membered heterocyclyl, C3-C 10 -cycloalkyl, and 5- to 14-membered heteroaryl.

[0068] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is 3- to 14-membered heterocyclyl.

[0069] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexanyl and piperidyl.

[0070] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is, in each occurrence, amino, hydroxy, C1-C6-alkyl, aminoC1-C6-alkyl-, hydroxy-C1-C6-alkyl-, (C1-C6-alkyl)2N-, (C1-C6-alkyl)2N-C1-C6-alkyl-, (C1-C6-alkyl)2N-C1-C6-alkyl-C(O)-, oxo, carbamoyl, carbamoyl-C1-C6-alkyl, carboxy, carboxy-C1-C6-alkyl, halogen, aminoalkyl-S(O)2- and the group [Chemical] independently selected from, R 6 , r, C and L 3 as defined herein, a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof is provided.

[0071] In a preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is independently selected from amino, hydroxy, and hydroxy-C1-C6-alkyl in each occurrence.

[0072] In a particularly preferred embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 5 is selected from amino, hydroxy, and hydroxymethyl in each occurrence.

[0073] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein L 3 is a covalent bond or a carbonyl.

[0074] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein r is 0 or 1.

[0075] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein C is C3-C 10 -cycloalkyl or a 3- to 14-membered heterocyclyl.

[0076] In one embodiment, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, wherein R 6 is hydroxy.

[0077] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, m is 1; R 1 is selected from amino, amino-C1-C6-alkoxy-, the group

Chemical formula

[0078] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, m is 1; R1 is a group [Chem.] and herein L 1 is selected from carbonyl, -CH2C(O)-, -CH2NHC(O)-, and -NHC(O)-; q is 0 or 1; B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexanyl, and piperidyl; and R 5 is selected from amino, hydroxy, and hydroxymethyl.

[0079] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 2 is selected from halogen and C1-6-alkyl.

[0080] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein n is 1 and R 2 is selected from chloro and ethyl.

[0081] In one embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is of the following formula (II): [Chem.] (wherein R 1 , R 2 , R 3 , R 4 , m and p are as defined herein).

[0082] In a preferred embodiment, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein R 3 is C1-C6-alkyl.

[0083] In a particularly preferred embodiment, the invention relates to R 3 being methyl, a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0084] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 1, 2, 3, or 4 and R 4 is, in each occurrence, independently selected from halogen, C1-C6-alkyl, C1-C6-alkoxy, cyano, halo-C1-C6-alkyl, cyano-C1-C6-alkyl, (C1-C6-alkyl)2N-, halo-C1-C6-alkoxy, cyano-C1-C6-alkoxy, C1-C6-alkoxy-C1-C6-alkoxy-, (C1-C6-alkyl)2N-C(O)-, and heteroaryloxy.

[0085] In a preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3 and R 4 is, in each occurrence, independently selected from halogen, C1-C6-alkoxy, halo-C1-C6-alkoxy, and cyano-C1-C6-alkoxy.

[0086] In a particularly preferred embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein p is 2 or 3 and R 4 is, in each occurrence, independently selected from fluoro, chloro, methoxy, FCH2O-, F2CHO-, and CNCH2O-.

[0087] In one embodiment, the invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) has the formula (III):

Chemical formula

[0088] In a preferred embodiment, the present invention provides a compound of formula (III) as described herein, or a pharmaceutically acceptable salt thereof, R 4a is halogen; R 4b is selected from hydrogen and halogen; R 4c is selected from C1-C6-alkoxy, cyano-C1-C6-alkoxy, and halo-C1-C6-alkoxy; R 4d is hydrogen.

[0089] In a particularly preferred embodiment, the present invention provides a compound of formula (III) as described herein or a pharmaceutically acceptable salt thereof, R 4a is selected from fluoro and chloro; R 4b is selected from hydrogen, fluoro and chloro; R 4c is selected from methoxy, FCH2O-, F2CHO- and CNCH2O-; R4d is hydrogen.

[0090] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, m is 1; R 1 is amino, amino-C1-C6-alkoxy-, the group

Chemical formula

[0091] In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, m is 1; R 1 is the group [Chemical formula] and wherein L 1 is selected from carbonyl, -CH2C(O)-, -CH2NHC(O)-, and -NHC(O)-; q is 0 or 1; B is a 3- to 14-membered heterocyclyl; R 5 is selected from amino, hydroxy, and hydroxy-C1-C6-alkyl-; n is 1; R 2 is selected from halogen and C1-C6-alkyl; R 3 is C1-C6-alkyl; p is 2 or 3; and, R 4 is independently selected, in each occurrence, from halogen, C1-C6-alkoxy, halo-C1-C6-alkoxy, and cyano-C1-C6-alkoxy.

[0092] In a particularly preferred embodiment, the present invention provides a compound of formula (I) as described herein or a pharmaceutically acceptable salt thereof, m is 1; R 1 is the group [Chemical formula] and wherein L 1 is selected from carbonyl, -CH2C(O)-, -CH2NHC(O)-, and -NHC(O)-; q is 0 or 1; B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexanyl, and piperidyl; R 5 is selected from amino, hydroxy, and hydroxymethyl; n is 1; R 2 is selected from chloro and methyl; R 3 is methyl; p is 2 or 3; and, R 4 is independently selected from fluoro, chloro, methoxy, FCH2O-, F2CHO- and CNCH2O- in each occurrence.

[0093] In one embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is: N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[2-(methylamino)ethyl]piperidine-4-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(aminomethyl)morpholine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S,4S)-4-Aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(3-Amino-2-hydroxy-propyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(morpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-(morpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2R)-2-(Aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(thiomorpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminoazetidine-1-carbonyl)piperidine 1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(5-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-Aminoethyl)-4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-(4-piperazin-1-ylsulfonylpiperidine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[[(2S)-pyrrolidine-2-carbonyl]amino]ethyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-piperidylsulfonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(2-amino-2-oxo-ethyl)amino]ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; (3R)-1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]pyrrolidine-3-carboxylic acid; 1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]azetidine-3-carboxylic acid; 5-[3-chloro-4-(cyanomethoxy)-2-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; 5-[2-chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-azetidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-pyrrolidin-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2R)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3R)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-hydroxyazetidin-3-yl)methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-Pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(3-hydroxyazetidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(pyrrolidin-3-ylmethyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(dimethylamino)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,5-trifluoro-4-methoxy-phenyl)imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[rac-(1S,5R)-3-azabicyclo[3.1.0]hexan-6-yl]piperidine-4-carboxamide; N-[4-[3-(2-Aminoethoxy)azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; 5-[2-Chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-Hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(5-Hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(azetidine-3-carbonyl)piperidine-4-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-2-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxyazetidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[1-(4-hydroxypiperidine-4-carbonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[3-(aminomethyl)azetidine-1-carbonyl]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 3-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propanoic acid; 4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]butanoic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(dimethylcarbamoyl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(aminomethyl)cyclobutanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-amino-2-oxo-ethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[rac-(3aR,6aS)-5-(piperidine-4-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(3-hydroxyazetidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]azetidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[3-(piperazine-1-carbonyl)azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aR,6aS)-5-[rac-(3R)-pyrrolidine-3-carbonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[[2-(dimethylamino)acetyl]amino]azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aS,6aR)-2-[2-(dimethylamino)acetyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,4-trifluorophenyl)imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[rac-(3aR,6aR)-2,3,3a,4,6,6a-Hexahydro-1H-pyrrolo[3,4-b]pyrrole-5-carbonyl]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-2,4-difluoro-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[[2-(dimethylamino)acetyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[3-(prop-2-ynylamino)propyl]piperidine-4-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-Aminoethyl)-1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]piperidine-4-carboxamide; 1-[4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[2-[2-(dimethylamino)ethoxy]ethyl]piperidine-4-carboxamide; 5-[4-(difluoromethoxy)phenyl]-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-(2-chloro-4-methoxyphenyl)-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-guanidinobutanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminopropanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(5-Aminopentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-cyanopropanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminopropanoylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-yl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[(1S,3R)-3-Aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethylsulfonylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidyl)piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-pyridylmethyl)piperidine-4-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]piperidine-4-carboxamide; 5-[3-Chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4R)-4-fluoropyrrolidin-3-yl]piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3S)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[4-[4-(2-aminoethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidin-3-ylmethoxy)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminobutanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[(2S)-2-Aminopropyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[1-(2-Aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-[2-(dimethylamino)acetyl]piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2-(difluoromethyl)-3-fluoro-4-methoxy-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(Pyrrolidin-3-ylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S)-3-Aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-Aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-(4-Piperidylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)azetidine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-carbamoyl pyrrolidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-aminoethylsulfonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(methanesulfonamide)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethylsulfonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(2-oxoimidazolidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(2-aminoethyl)azetidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2-pyrrolidin-3-ylacetyl)amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-(fluoromethoxy)-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methylphenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S,4S)-3-amino-4-fluoropyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-(4-pyrrolidin-3-ylsulfonylpiperidine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminobicyclo[1.1.1]pentane-1-carbonyl]piperazine-1-carbonyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[[(1-methyl-4-piperidyl)amino]carbamoyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2-cyano-3-fluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(5-oxopyrrolidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)propanoylamino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[3-Chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidylmethyl)piperidine-4-carboxamide; N-[4-[4-[3-(Aminomethyl)azetidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminoazetidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-[2-(2-Aminoethoxy)ethoxy]propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(5-oxopyrrolidin-2-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(5-oxopyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(methylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(6-oxopiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-azaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxyphenyl)-N-[3-chloro-4-[4-[(2R,4R)-4-hydroxypyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[6-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]-2-azaspiro[3.3]heptane-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propanoyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxyphenyl)-1-methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[3-[[rac-(3R)-pyrrolidine-3-carbonyl]amino]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[(1S)-2-Amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]pyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[2-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2-fluoro-3,4-dimethoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(2,5-dioxoimidazolidin-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[3-(2-aminoethoxy)propanoylamino]pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; 2-[4-[4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetic acid; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-methoxyethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-pyridyloxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(4-pyridyloxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3,4-difluoro-5-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethyl)-2-fluorophenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methylphenyl]-9-methoxy-6,7-dihydro-5H-imidazo[5,1-a][2]benzazepine-3-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(2-aminoethoxy)propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[atags2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidyl)piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-atags2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidyl)piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; N-[4-[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[(2-aminoacetyl)amino]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-carbamoylcyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxycyclobutanecarbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-methoxypropanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(3-amino-3-oxopropoxy)propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; and

[0094] selected from N-[4-[4-(5-amino-5-oxopentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide. In a preferred embodiment, the present invention provides a compound of formula (I) described herein or a pharmaceutically acceptable salt thereof, wherein the compound of formula (I) is: N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; 5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-(2-pyrrolidin-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; 4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[3-chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[4-[4-[(2S,4S)-4-aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; and 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide selected from.

[0095] In one embodiment, the present invention provides a pharmaceutically acceptable salt of the compound of formula (I) described herein, particularly a pharmaceutically acceptable salt selected from hydrochloride, fumarate, lactate (particularly derived from L-(+)-lactic acid), tartrate (particularly derived from L-(+)-tartaric acid) and trifluoroacetate. In a further particular embodiment, the present invention provides the compound of formula (I) described herein (i.e., as the respective "free base" or "free acid").

[0096] In some embodiments, the compounds of formula (I) are isotopically labeled by replacing one or more atoms therein with atoms having different atomic masses or mass numbers. Such isotopically labeled (i.e., radiolabeled) compounds of formula (I) are considered to be within the scope of the present disclosure. Exemplary isotopes that can be incorporated into the compounds of formula (I) include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively, such as 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I, but are not limited thereto. Certain isotopically labeled compounds of formula (I), such as those incorporating a radioisotope, are useful in drug and / or substrate tissue distribution studies. The radioisotopes tritium, i.e., 3 H and carbon-14, i.e., 14 C, are particularly useful for this purpose in view of their ease of incorporation and means of immediate detection. For example, the compounds of formula (I) can be enriched to 1, 2, 5, 10, 25, 50, 75, 90, 95, or 99% of a given isotope.

[0097] Replacement with heavier isotopes, such as deuterium, i.e., 2 H, etc., can result in higher metabolic stability, for example, a longer in vivo half-life or a lower required dose, thereby providing certain therapeutic advantages.

[0098] 11 C, 18 F, 15 O and 13Substitution with a positron-emitting isotope such as N can be useful in positron emission tomography (PET) studies for examining receptor occupancy of a substrate. The isotopically labeled compound of formula (I) can generally be prepared by conventional techniques known to those skilled in the art or by a process similar to that described in the examples below using a suitable isotopically labeled reagent in place of the previously used unlabeled reagent.

[0099] Manufacturing process The preparation of the compounds of formula (I) of the present invention can be carried out by sequential or convergent synthetic routes. The synthesis of the compounds of the present invention is shown in the following schemes. The skills necessary for carrying out the reactions and purification of the obtained products are known to those skilled in the art. The substituents and indices used in the following process descriptions have the meanings shown previously herein unless otherwise indicated. More specifically, the compounds of formula (I) can be prepared by the methods shown below, the methods shown in the examples, or similar methods. Appropriate reaction conditions for the individual reaction steps are known to those skilled in the art. Also, for the reaction conditions described in the literature that affect the described reactions, see, for example: Comprehensive Organic Transformations: A Guide to Functional Group Preparations, 3rd Edition, Richard C. Larock. John Wiley & Sons, New York, NY. 2018). The inventors have found it convenient to carry out the reactions in the presence or absence of a solvent. Regarding the nature of the solvent used, there is no particular limitation as long as it does not adversely affect the reaction or the reagents involved and it can dissolve the reagents to at least some extent. The described reactions can occur over a wide range of temperatures, and the exact reaction temperature is not critical to the present invention. It is convenient to carry out the described reactions in the temperature range between -78 °C and the reflux temperature. The time required for the reaction can also vary widely depending on many factors, especially the reaction temperature and the nature of the reagents. However, a period of 0.5 hours to several days will usually be sufficient to obtain the described intermediates and compounds. The order of the reactions is not limited to that shown in the schemes, but the order of the reaction steps can be freely changed depending on the starting materials and their respective reactivities. The starting materials can be commercially available or can be prepared by methods similar to those shown below, the methods described in the references or examples cited herein, or methods known in the art.

[0100] All substituents, especially R 2 -R 4Unless otherwise stated, it is as defined above and in the claims. Further, unless otherwise explicitly stated, all reactions, reaction conditions, abbreviations, and symbols have meanings well-known to those skilled in organic chemistry. [Chem.]

[0101] Here, Ra is alkyl, especially Me, Et, or iso-butyl.

[0102] The type I intermediate can be prepared according to Scheme 1. 5-Bromo-1-methyl-imidazole can be acylated with isobutyl carbonochloridate in basic conditions, e.g., with DIPEA in DCM, to obtain Ia (step a). The acid Ib can be obtained by hydrolyzing Ia at room temperature using an appropriate base and an appropriate solvent (e.g., K2CO3 in EtOH / H2O) (step b). The type I intermediate is obtained by amide coupling of Ib and amine Ic with a condensing agent, e.g., CDI, DCC, HATU, HBTU, T3P, in an appropriate solvent, e.g., DMF, DMA, or dioxane, optionally in the presence of a base, e.g., NEt3, DIPEA, or DMAP (step c). [Chem.] Here, Ra is alkyl, especially Me, Et, or iso-butyl.

[0103] Here, "component X" is a cyclic amine with or without PG, and "PG" means an appropriate protecting group such as a Cbz or Boc protecting group.

[0104] The Type VI intermediate or the Type I example can be prepared according to Route 1 of Scheme 2. Hydrolysis of the Type I intermediate at room temperature using a suitable base and a suitable solvent (e.g., LiOH or NaOH in EtOH / H2O) gives the Type II intermediate (Step 1a). For example, applying the method described in Scheme 3, Step 3b, this intermediate is subjected to amide coupling with Component X and Component Y (XIII-type intermediate), and then (if necessary) the PG of Y is deprotected to obtain the Type IX intermediate or the Type II example (Step 2a).

[0105] In Route 3, the acidic compound (Type IV intermediate) is known in the art and can be subjected to amide coupling with Component X-Y (Type VII intermediate), for example, by applying the method described in Scheme 1, Step C. Then, (if necessary) the PG of X-Y is deprotected and the compound of the Type IX intermediate or the Type II example is obtained by applying the method described in Scheme 2, Step 1C, for example (Step 3a).

[0106] The compound of formula (Type III example) can be prepared according to three routes outlined in Scheme 3.

Chemical formula

[0107] Here, X is a cyclic amine with or without PG, and "PG" means a suitable protecting group such as a Cbz or Boc protecting group.

[0108] Here, Component Q is an amine with or without PG, and "PG" means a suitable protecting group such as a Cbz or Boc protecting group.

[0109] Here, Component Y-Q of Route 2 is an acid (Y)-amine (Q) compound with or without PG, and "PG" means a suitable protecting group such as a Cbz or Boc protecting group.

[0110] Here, the component X-Y-Q of Route 3 is an alkyl halide (Y) bonded to two amine (X - cyclic amine and Q) compounds with or without PG, where "PG" means a suitable protecting group such as a Cbz or Boc protecting group.

[0111] In Route 1, the removal of the protecting group (if necessary) from the Type IX intermediate is known in the art and can be achieved, for example, by applying the method described in Scheme 2, Step 1C. Then, a Type III example is obtained by amide coupling with component Q (Ig) using the method described in Scheme 3, Step 3b (Step 1a).

[0112] In Route 2, the removal of the protecting group (if necessary) from the Type VI intermediate is known in the art and can be achieved, for example, by applying the method described in Scheme 2, Step 1C. Then, a Type III example is obtained by amide coupling with component Y-Q (Type X intermediate) using the method described in Scheme 3, Step 3b (Step 2a).

[0113] In Route 3, amide coupling between the acidic compound (Type IV intermediate) and component X-Y-Q (Type VIII intermediate) can be carried out using the method described in Scheme 3, Step 3b, for example. Then, the protecting group is removed (if necessary) by applying the method known in the art and described in Scheme 2, Step 1C to obtain a Type III example.

[0114] In one aspect, the present invention provides a method for producing a compound of formula (I) described herein, which is the method described in any one of Schemes 1 - 5 above.

[0115] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, when produced according to the method described herein.

[0116] Use of the compounds of the present invention As shown in the experimental section, the compounds of formula (I) and their pharmaceutically acceptable salts have valuable pharmacological properties for the treatment or prevention of infectious diseases and diseases resulting therefrom, particularly bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, caused by pathogens, particularly bacteria, more particularly by Acinetobacter species, and most particularly by Acinetobacter baumannii.

[0117] The compounds of formula (I) and their pharmaceutically acceptable salts are active as antibiotics, particularly as antibiotics against Acinetobacter species, more specifically as antibiotics against Acinetobacter baumannii, and most specifically as pathogen-specific antibiotics against Acinetobacter baumannii.

[0118] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as antibiotics, i.e., as suitable antibacterial pharmaceutical ingredients in the treatment and prevention of bacterial infections, particularly in the treatment and prevention of bacterial infections caused by Acinetobacter species, more specifically in the treatment and prevention of bacterial infections caused by Acinetobacter baumannii.

[0119] The compounds of the present invention can be used alone or in combination with other drugs for the treatment or prevention of infectious diseases and resulting diseases, particularly bacteremia, pneumonia, meningitis, urinary tract infections, and wound infections, caused by pathogens, particularly bacteria, more particularly by Acinetobacter species, and most particularly by Acinetobacter baumannii.

[0120] In one aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use as a therapeutically active substance.

[0121] In a further aspect, the present invention provides a compound of formula (I) described herein, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

[0122] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and diseases caused thereby.

[0123] In certain embodiments, the nosocomial infection and diseases caused thereby are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or combinations thereof.

[0124] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases caused thereby.

[0125] In certain embodiments, the infection and diseases caused thereby caused by Gram-negative bacteria are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, or combinations thereof.

[0126] In a further aspect, the present invention provides a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof and diseases resulting therefrom.

[0127] In a further aspect, the present invention provides a method for the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or combinations thereof and diseases resulting therefrom, the method comprising administering to a mammal a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof.

[0128] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, as an antibiotic.

[0129] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and the resulting disease.

[0130] In a further aspect, the present invention provides the use of a compound of formula (I) as described herein, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof and the resulting disease.

[0131] In certain embodiments, the infectious disease and the resulting disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli or a combination thereof are selected from bacteremia, pneumonia, meningitis, urinary tract infection and wound infection or a combination thereof.

[0132] In a further aspect, the present invention provides those pharmaceutically acceptable salts as defined above for use in the treatment or prevention of infectious diseases and the resulting diseases, in particular bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, caused by pathogens, in particular bacteria, more specifically by Acinetobacter species, most specifically by Acinetobacter baumannii.

[0133] In a further aspect, the present invention provides a method for the treatment or prevention of an infection caused by a pathogen, in particular a bacterium, more specifically an infection caused by Acinetobacter species, most specifically Acinetobacter baumannii, and the resulting diseases, in particular bacteremia, pneumonia, meningitis, urinary tract infection and wound infection, which comprises administering to a mammal a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof.

[0134] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of an infection caused by a pathogen, in particular a bacterium, more specifically an infection caused by Acinetobacter species, most specifically Acinetobacter baumannii, and the resulting diseases, in particular bacteremia, pneumonia, meningitis, urinary tract infection and wound infection.

[0135] In a further aspect, the present invention provides the use of a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament for the treatment or prevention of an infection caused by a pathogen, in particular a bacterium, more specifically an infection caused by Acinetobacter species, most specifically Acinetobacter baumannii, and the resulting diseases, in particular bacteremia, pneumonia, meningitis, urinary tract infection and wound infection. Such a medicament comprises a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof.

[0136] Pharmaceutical Compositions and Administration In one aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) as defined above or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable additives. Exemplary pharmaceutical compositions are described in Examples A - D.

[0137] In a further aspect, the present invention relates to a compound of formula (I) as defined above, or a pharmaceutically acceptable salt thereof, for the treatment or prevention of infections and resulting diseases caused by pathogens, in particular by bacteria, more specifically by Acinetobacter species, most specifically by Acinetobacter baumannii, in particular bacteremia, pneumonia, meningitis, urinary tract infections and wound infections, and a pharmaceutical composition comprising the same and one or more pharmaceutically acceptable excipients.

[0138] The compounds of formula (I) and their pharmaceutically acceptable salts can be used as medicaments (for example in the form of pharmaceutical preparations). Pharmaceutical formulations can be administered in vivo orally (for example in the form of tablets, coated tablets, dragees, hard gelatin capsules and soft gelatin capsules, solutions, emulsions or suspensions), nasally (for example in the form of nasal sprays), or rectally (for example in the form of suppositories), etc. However, administration can also be carried out parenterally, for example intramuscularly or intravenously (for example in the form of injection solutions or infusions).

[0139] The compounds of formula (I) and their pharmaceutically acceptable salts can be processed with pharmaceutically inert inorganic or organic additives for the manufacture of tablets, coated tablets, dragees, and hard gelatin capsules. Lactose, corn starch or its derivatives, talc, stearic acid or its salts, etc. can be used, for example, as such additives for tablets, dragees and hard gelatin capsules.

[0140] Additives suitable for soft gelatin capsules are, for example, vegetable oils, waxes, fats, semi-solid substances, and liquid polyols, etc.

[0141] Additives suitable for the manufacture of solutions and syrups are, for example, water, polyols, sucrose, invert sugar, glucose, etc.

[0142] Suitable additives for injection solutions are, for example, water, alcohol, polyols, glycerol, vegetable oils, etc.

[0143] Additives suitable for suppositories are, for example, natural oils or hardened oils, waxes, fats, semi-solid or liquid polyols, and the like.

[0144] Furthermore, the pharmaceutical preparation can contain preservatives, solubilizers, viscosity-increasing substances, stabilizers, wetting agents, emulsifiers, sweeteners, coloring agents, flavoring agents, salts for changing the osmotic pressure, buffering agents, masking agents, or antioxidants. It can also contain other therapeutically useful substances.

[0145] The dosage can vary widely and, of course, is adapted to the individual requirements in each particular case. Generally, in the case of oral administration, a daily dosage of about 0.1 mg to 20 mg / kg body weight, preferably about 0.5 mg to 4 mg / kg body weight (e.g., about 300 mg / person), is preferably divided into 1 to 3 individual dosages and can, for example, be composed of the same amount. However, it is clear that, where indicated, it can exceed the upper limit given in this specification.

[0146] Co-administration of the compound of formula (I) with other agents The compound of formula (I) or its salt or the compounds disclosed herein or their pharmaceutically acceptable salts can be used for treatment alone or in combination with other agents. For example, the second agent in a combination pharmaceutical formulation or dosing regimen can have complementary activity to the compound of formula (I) so as not to have an adverse effect on each other. The compounds can be administered together or separately within one pharmaceutical composition. In one embodiment, the compound or pharmaceutically acceptable salt can be co-administered with an antibiotic, in particular, an antibiotic for the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and diseases resulting therefrom.

[0147] The term "co-administering" refers to the simultaneous administration, or separate sequential administration in any manner, of one or more additional pharmaceutical active ingredients, including a compound of formula (I) or a salt thereof or a compound disclosed herein or a pharmaceutically acceptable salt thereof, and an antibiotic formulation. If the administrations are not simultaneous, the compounds are administered in close temporal proximity to each other. Further, it is not important whether the compounds are administered in the same dosage form; for example, one compound may be administered intravenously and another compound may be administered orally.

[0148] Typically, agents having antibacterial activity may be co-administered. Specific examples of such agents are carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam + dulobactam, cefiderocol (fetroja), macrolide peptide, and macrolide (erythromycin), as exemplified, for example, in International Publication No. WO2017072062, International Publication No. WO2019185572, and International Publication No. WO2019206853.

[0149] In one aspect, the present invention provides a pharmaceutical composition described herein further comprising an additional therapeutic agent.

[0150] In one embodiment, the additional therapeutic agent is an antibiotic formulation.

[0151] In one embodiment, the additional therapeutic agent is an antibiotic formulation useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

[0152] In one embodiment, the additional therapeutic agent is an antibiotic preparation selected from carbapenem (meropenem), fluoroquinolone (ciprofloxacin), aminoglycoside (amikacin), tetracycline (tigecycline), colistin, sulbactam, sulbactam + dulobactam, cefiderocol (fetroja), macrocyclic peptide, and macrolide (erythromycin), as exemplified in International Publication No. WO2017072062, International Publication No. WO2019185572, and International Publication No. WO2019206853.

Example

[0153] The present invention will be more fully understood by reference to the following examples. However, the claims should not be construed as being limited to the scope of these examples.

[0154] When the preparation example is obtained as a mixture of enantiomers, the pure enantiomers can be separated by the methods described herein or by methods known to those skilled in the art, such as chiral chromatography (e.g., chiral SFC) or crystallization.

[0155] Unless otherwise specified, all reaction examples and intermediates were prepared under an argon atmosphere.

[0156] The abbreviations used herein are as follows: ACN or MeCN Acetonitrile BINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphthalene CFU Colony-forming unit d Day DCM Dichloromethane DIPEA N,N-Diisopropylethylamine EtOAc or EA Ethyl acetate FA Formic acid h(plural available) or hr(plural available) Hour HATU: 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate HPLC: High Performance Liquid Chromatography HPLC-UV: High Performance Liquid Chromatography with Ultraviolet Detector IC50: Median Inhibitory Concentration IC90: 90% Inhibitory Concentration PE: Petroleum Ether PdCl2(DPPF): Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) PG: Protecting Group Pre-cat: Pre-catalyst Preparative HPLC: Preparative High Performance Liquid Chromatography RBF: Round Bottom Flask rt: Room Temperature sat: Saturated SEM: 2-Methoxyethyl(trimethyl)silane FA: Formic Acid TFA: Trifluoroacetic Acid wt: Weight X-PHOS: 2-Dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl

[0157] Intermediate I: 308 Methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate

Chem.

[0158] Step 1: Isobutyl 5-bromo-1-methyl-imidazole-2-carboxylate

[0159] A solution of 5-bromo-1-methyl-imidazole (20 g, 124 mmol) and DIPEA (32.1 g, 43.4 mL, 248 mmol) in DCM (140 mL) at -70 °C was slowly added dropwise within 30 minutes to a solution of isobutyl carbonochloridate (22.1 g, 161 mmol) in DCM (60 mL). The mixture was stirred at -70 °C for 2 hours. Next, the mixture was slowly warmed to room temperature and stirred overnight. Then, the solution was washed with water and concentrated in vacuo. Subsequently, the crude product was purified by flash column chromatography to obtain isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g, yield 89.4%) as a yellow oil. MS (ESI, m / z): 261.2 [M+H] +

[0160] Step 2: 5-Bromo-1-methyl-imidazole-2-carboxylic acid To a solution of isobutyl 5-bromo-1-methyl-1H-imidazole-2-carboxylate (29 g, 111 mmol) in MeOH (5 mL) and THF (120 mL) was added a solution of lithium hydroxide monohydrate (9.32 g, 222 mmol) in water (60 mL). The mixture was stirred at room temperature for 3 hours. The organic solvents were removed under reduced pressure. 12N aqueous HCl was added with stirring to pH 4 - 5. The white solid was filtered, washed with MeOH, and dried to obtain 5-bromo-1-methyl-imidazole-2-carboxylic acid (20.5 g, yield 90%) as a white solid. MS (ESI, m / z): 204.8 [M+H] +

[0161] Step 3: Methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate A mixture of 5-bromo-1-methyl-1H-imidazole-2-carboxylic acid (13 g, 63.4 mmol), methyl 2-chloro-4-(methylamino)benzoate (11.8 g, 63.4 mmol), HATU (24.1 g, 63.4 mmol) and DIPEA (24.6 g, 33.2 mL) in DMF (30 mL) was stirred at room temperature overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM (3 x 50 mL). The combined organic phases were washed with water, dried over anhydrous Na2SO4 and concentrated in vacuo. A solid precipitated from the concentrated solution. The solid was collected, washed with MeOH and dried to give methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (18 g, 76% yield) as a pale yellow solid. MS (ESI, m / z): 371.8 [M+H] +

[0162] The following type I intermediates were prepared in the same manner as intermediate 308.

Table 1

[0163] Type II intermediate: 313 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoic acid

Chem.

[0164] A solution of lithium hydroxide monohydrate (2.57 g, 61.2 mmol) in water (24 mL) was added to a solution of methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (7.6 g, 20.4 mmol) in MeOH (2 mL) and THF (48 mL). The mixture was stirred overnight at room temperature. The mixture was then concentrated, and the aqueous layer was acidified with 6 N aqueous HCl. A solid precipitated from the concentrated solution. The solid was collected, washed with water, and dried to give 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoic acid as a white solid (6 g, 82% yield). MS (ESI, m / z): 358.0 [M+H] +

[0165] The following type II intermediates were prepared in the same manner as intermediate 313.

Table 2

[0166] Type III intermediate: 315 2-(4-(Difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane

Chemical formula

[0167] Step 1: 1-Bromo-4-(difluoromethoxy)-2,3-difluorobenzene

[0168] A solution of 4-bromo-2,3-difluorophenol (25 g, 120 mmol), sodium 2-chloro-2,2-difluoroacetate (36.5 g, 239 mmol) and K2CO3 (19.8 g, 144 mmol) in DMF (250 mL) and water (57 mL) was stirred at 100 °C for 3.0 h under N2. The reaction mixture was poured into 1.5 L of H2O and extracted with EtOAc (3 × 250 mL). The combined organic layers were washed with saturated NaCl (1 x 200 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 120 g, 0% - 20% DCM in PE) to give 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25.2 g, 97.3 mmol, 81.3% yield).

[0169] Step 2: 2-(4-(Difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a 250 mL RBF were added 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (24.5 g, 96.5 mmol), 1-bromo-4-(difluoromethoxy)-2,3-difluorobenzene (25 g, 96.5 mmol), PdCl2(DPPF)-CH2Cl2 adduct (3.53 g, 4.83 mmol) and potassium acetate (18.9 g, 193 mmol) in dioxane (150 mL). The mixture was stirred at 80 °C for 15 h under N2. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50 mL of H2O and extracted with EtOAc (3 × 50 mL). The combined organic layers were washed with saturated NaCl (1 × 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 330 g, 0% - 20% DCM in PE) to give 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (25 g, 81.7 mmol, 84.6% yield).

[0170] The following type III intermediate was prepared in the same manner as intermediate 315. [Table 3]

[0171] Type III intermediate: 319 2-[2,3-Difluoro-4-(fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane [Chemical formula]

[0172] Step 1: 1-Bromo-2,3-difluoro-4-(fluoromethoxy)benzene

[0173] To a 5 mL microwave vial were added 4-bromo-2,3-difluorophenol (150 mg, 718 μmol, 1 equivalent), fluoromethyl 4-methylbenzenesulfonate (176 mg, 861 μmol), and Cs2CO3 (351 mg, 1.08 mmol) in DMF (3 mL). The vial was capped and heated overnight at 90 °C in a microwave. The reaction mixture was poured into 50 mL of H2O and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated NaCl (1 × 50 mL), then dried over Na2SO4 and concentrated in vacuo to give 1-bromo-2,3-difluoro-4-(fluoromethoxy)benzene (153 mg, 635 μmol, 88.4% yield).

[0174] Step 2: 2-[2,3-Difluoro-4-(fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane To a 5 mL microwave vial were added bis(pinacolato)diboron (161 mg, 635 μmol), 1-bromo-2,3-difluoro-4-(fluoromethoxy)benzene (153 mg, 635 μmol), PdCl2(DPPF)-CH2Cl2 adduct (46.5 mg, 63.5 μmol) and potassium acetate (125 mg, 1.27 mmol) in dioxane (3 mL). The vial was placed under nitrogen, capped and heated overnight at 80 °C by microwave. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of H2O and extracted with EtOAc (3 × 25 mL). The combined organic layers were washed with saturated NaCl (1 × 25 mL), then dried over Na2SO4 and concentrated in vacuo to give 2-[2,3-difluoro-4-(fluoromethoxy)phenyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (180 mg, 625 μmol, 98.4% yield).

[0175] The following type III intermediates were prepared in the same manner as intermediate 319. [Table 4]

[0176] Type III intermediate: 322 4,4,5,5-Tetramethyl-2-(2,3,5-trifluoro-4-methoxy-phenyl)-1,3,2-dioxaborolane [Chemical formula]

[0177] Step 1: 4-Bromo-2,3,6-trifluorophenol

[0178] In a 100 mL round-bottom flask, 2,3,6-trifluorophenol (215 mg, 1.45 mmol) was combined with CHCl3 (10 mL) to obtain a colorless solution. NBS (284 mg, 1.6 mmol) was added at 0 °C. While stirring the reaction mixture, it was warmed to room temperature over 2 hours. The crude reaction mixture was concentrated in vacuo to afford 4-bromo-2,3,6-trifluorophenol (330 mg, 1.45 mmol, yield 100%), which was used directly in the next step. (ESI, m / z): 227.0 [M-H]-.

[0179] Step 2: 1-Bromo-2,3,5-trifluoro-4-methoxybenzene In a 100 mL round-bottom flask, 4-bromo-2,3,6-trifluorophenol (330 mg, 1.45 mmol), MeI (413 mg, 182 μl, 2.91 mmol) and K2CO3 (301 mg, 2.18 mmol) were combined with acetonitrile (10 mL) to obtain a pale yellow solution. The reaction mixture was heated to 50 °C and stirred for 2 hours. The reaction mixture was filtered through glass fiber paper. The crude material was purified by flash chromatography to afford 1-bromo-2,3,5-trifluoro-4-methoxybenzene (220 mg, 913 μmol, yield 62.8%).

[0180] Step 3: 4,4,5,5-Tetramethyl-2-(2,3,5-trifluoro-4-methoxy-phenyl)-1,3,2-dioxaborolane To a 100 mL microwave vial were added 1-bromo-2,3,5-trifluoro-4-methoxybenzene (220 mg, 913 μmol) in dioxane (10 mL), 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (255 mg, 1 mmol), Pd2(dba)3 (83.6 mg, 91.3 μmol), X-PHOS (87 mg, 183 μmol) and potassium acetate (269 mg, 171 μl, 2.74 mmol). The vial was placed under N2, capped and heated by microwave at 100 °C for 2 hours. The reaction mixture was used directly in the next step without further purification.

[0181] Intermediate of Type III: 323 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline

Chemical formula

[0182] Step 1: 4-Bromo-2,3-difluoro-N,N-dimethylaniline In a 100 mL round-bottom flask, 4-bromo-2,3-difluoroaniline (300 mg, 1.44 mmol), formaldehyde (433 mg, 397 μL, 14.4 mmol) and formic acid (6.64 g, 5.53 mL, 144 mmol) were combined to obtain a light red solution. The reaction mixture was heated to 50 °C and stirred for 3 hours. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50 mL of saturated NaHCO3 and extracted with EtOAc (3×25 mL). The combined organic layers were washed with saturated NaCl (1×25 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash chromatography to obtain 4-bromo-2,3-difluoro-N,N-dimethylaniline (270 mg, 1.14 mmol, yield 79.3%). (ESI, m / z): 238.0 [M+H]+.

[0183] Step 2: 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline In a 100 mL round-bottom flask, 4,4,4’,4’,5,5,5’,5’-octamethyl-2,2’-bi(1,3,2-dioxaborolane) (70.5 mg, 277 μmol), 4-bromo-2,3-difluoro-N,N-dimethylaniline (65.5 mg, 277 μmol), PdCl2(DPPF)-CH2Cl2 adduct (20.3 mg, 27.7 μmol) and potassium acetate (81.7 mg, 832 μmol) were combined with dioxane (12 mL) to obtain a light brown solution under N2. The reaction mixture was heated to 100 °C and stirred for 5 hours. The reaction mixture was used directly in the next step.

[0184] Intermediate of type III: 324 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide [Chemical formula]

[0185] Step 1: 4-Bromo-2,3-difluoro-N,N-dimethylbenzamide In a 100 mL round-bottom flask, 4-bromo-2,3-difluorobenzoic acid (300 mg, 1.27 mmol), dimethylamine (in THF) (1.9 mL, 3.8 mmol), and DIEA (327 mg, 442 μL, 2.53 mmol) were combined with DMF (5 mL) to obtain a colorless solution. HATU (578 mg, 1.52 mmol) was added. The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into 100 mL of H2O and extracted with EtOAc (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 25 mL), then dried over Na2SO4 and concentrated in vacuo to obtain 4-bromo-2,3-difluoro-N,N-dimethylbenzamide (334 mg, 1.26 mmol, yield 99.9%). (ESI, m / z): 264.0 [M+H]+.

[0186] Step 2: 2,3-Difluoro-N,N-dimethyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide To a 25 mL microwave vial were added bis(pinacolato)diboron (70.7 mg, 278 μmol), 4-bromo-2,3-difluoro-N,N-dimethylbenzamide (70 mg, 265 μmol), Pd2(dba)3 (24.3 mg, 26.5 μmol), X-PHOS (25.3 mg, 53 μmol), and potassium acetate (78 mg, 795 μmol) in dioxane (6 mL). The vial was capped and heated in a microwave at 100 °C for 3 hours under N2. The reaction mixture was used directly in the next step.

[0187] Type III Intermediate: 325 2-[2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile

Chem.

[0188] Step 1: 2-(4-Bromo-2-chloro-phenoxy)acetonitrile A mixture of 4-bromo-2-chlorophenol (3 g, 14.5 mmol), 2-bromoacetonitrile (2.08 g, 17.4 mmol) and K2CO3 (3 g, 21.7 mmol) in acetone (30 mL) was stirred at 60 °C for 3 hours and then filtered. The solid was washed with EtOAc. The organic phase was washed with water, dried and concentrated to give the title compound (3.5 g, yield 98.2%) as a yellow oil.

[0189] Step 2: 2-[2-Chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile A mixture of 2-(4-bromo-2-chlorophenoxy)acetonitrile (3.5 g, 14.2 mmol), 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2-dioxaborolane (3.61 g, 14.2 mmol), potassium acetate (2.79 g, 28.4 mmol) and 1,1’-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (1.74 g, 2.13 mmol) in 1,4-dioxane (30 mL) was stirred at 80 °C overnight. The mixture was then filtered. Water (10 mL) was added. The aqueous layer was extracted with DCM. The organic layer was concentrated and the residue was purified by flash column chromatography to give the title compound (2.8 g, yield 67.2%). MS(ESI, m / z): 293.7 [M+H]+

[0190] The following Type III intermediates were prepared in the same manner as Intermediate 325:

Table 5-1

Table 5-2

Table 5-3

[0191] Type IV Intermediate: 341 2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid

Chemical formula

[0192] Step 1: Methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoate (Type V Intermediate) A mixture of methyl 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoate (Intermediate 308, 1 g, 2.68 mmol), (2,3-difluoro-4-methoxyphenyl)boronic acid (504 mg, 2.68 mmol), Na2CO3 (853 mg, 8.05 mmol) and 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (350 mg, 537 μmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was irradiated under microwave at 100 °C for 60 minutes. This operation was carried out a total of 8 times. The individual reaction mixtures were combined and concentrated in vacuo. Water (40 mL) was added. The aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried over anhydrous Na2SO4, concentrated, and the solid was dried to give the crude title compound (8.3 g) as a brown solid. MS (ESI, m / z): 435.9 [M+H] +

[0193] Project 2: 2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid To a solution of methyl 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoate (8.3 g, 19 mmol) in MeOH (2 mL), THF (48 mL) and water (24 mL) was added a solution of lithium hydroxide monohydrate (3.2 g, 76.2 mmol) in water (24 mL). The mixture was stirred at room temperature overnight. The mixture was then concentrated and acidified with 6N HCl with stirring until pH 3 - 4. Some solid precipitated from the concentrated solution. The solid was filtered to give the title compound (7 g, yield 87%) as a brown solid. MS (ESI, m / z): 422.3 [M+H] +

[0194] The following type-IV intermediates were prepared in the same manner as intermediate 341.

Table 6-1

Table 6-2

Table 6-3

Table 6-4

[0195] Type-VI intermediate: 362 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid

Chemical formula

[0196] Project 1: Methyl 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylate A mixture of 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (Intermediate 341, 3 g, 7.11 mmol), methyl piperidine-4-carboxylate (1.22 g, 8.54 mmol), DIPEA (2.76 g, 3.73 mL, 21.3 mmol) and 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (3.39 g, 10.7 mmol) in DMF (10 mL) was stirred at 25 °C overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM. The combined organic phases were dried over anhydrous Na2SO4, concentrated, and the title compound (3 g, yield 77.1%) was obtained as a black oil. MS (ESI, m / z): 547.47 [M+H] +

[0197] Project 2: 1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid A mixture of methyl 1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperidine-4-carboxylate (3.5 g, 6.4 mmol) and lithium hydroxide monohydrate (1.07 g, 25.6 mmol) in THF (12 mL), water (6 mL) and MeOH (0.5 mL) was stirred at room temperature overnight. The mixture was then acidified to pH 2 - 3 with 6 N HCl with stirring. The mixture was concentrated and the aqueous phase was extracted with DCM. The combined organic phases were washed with water, dried, and concentrated to give the title compound (2.8 g, yield 82%) as a black solid. MS (ESI, m / z): 533.60[M+H] +

[0198] The following type VI intermediates were prepared in the same manner as Intermediate 362: [Table 7-1] [Table 7-2]

[0199] Type VI Intermediate: 373 N-[4-(4-Aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide [Chemical Formula]

[0200] Step 1: tert-Butyl N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]carbamate A mixture of tert-butyl piperidin-4-ylcarbamate (684 mg, 3.41 mmol), 2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (Intermediate ********, 1.2 g, 2.85 mmol), HATU (1.3 g, 3.41 mmol) and DIPEA (1.1 g, 1.49 mL, 8.54 mmol) in DMF (10 mL) was stirred at room temperature for 2 hours. The mixture was then poured into water. The solid was collected, dried to give the title compound (1.5 g, yield 87.3%) as a brown solid. MS (ESI, m / z): 604.3 [M+H] +

[0201] Step 2: N-[4-(4-Aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide At room temperature, a solution of tert-butyl N-[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]carbamate (1.5 g, 2.48 mmol) in DCM (10 mL) and TFA (10 mL) was stirred for 1 hour. Under ice-cooling, the solution was basified to pH 8 - 9 with NH3·H2O. The aqueous layer was extracted with DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated to obtain the crude title compound (900 mg, yield 66%) as a black solid. MS(ESI, m / z): 504.2[M+H] +

[0202] The following type VI intermediates were prepared in the same manner as intermediate 373:

Table 8-1

Table 8-2

Table 8-3

Table 8-4

[0203] Type VI intermediate: 392 N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamide

Chemical Structure

[0204] Step 1 tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxylate To a 25 mL microwave vial, tert-butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate (1 g, 1.9 mmol), 2-(2,3-difluoro-4-(fluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (602 mg, 2.09 mmol), 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (124 mg, 190 μmol) and Na2CO3 (604 mg, 5.69 mmol) were added in dioxane (18 mL) / water (3 mL). The vial was capped and heated at 100 °C for 2 h under N2 in a microwave. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography to give tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (759 mg, 1.25 mmol, 65.8% yield). MS(ESI,m / z):608.2[M+H] +

[0205] Step 2 Intermediate 392 N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamide In a 100 mL round-bottom flask, tert-butyl 4-(2-chloro-4-(5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxylate (759 mg, 1.25 mmol) was combined with THF (8 mL) to obtain a dark brown solution. HCl (4.16 mL, 49.9 mmol) was added. The reaction mixture was stirred at room temperature for 10 minutes. The crude reaction mixture was concentrated in vacuo to give N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-(fluoromethoxy)phenyl)-1-methyl-1H-imidazole-2-carboxamide (634 mg, yield 80%), which was used directly in the next step. MS (ESI, m / z): 508.2 [M+H] +

[0206] The following type VI intermediates were prepared in the same manner as intermediate 392:

Table 9-1

Table 9-2

[0207] Type VII intermediate: 402 tert-butyl N-[2-(4-piperidyloxy)ethyl]carbamate

Chem.

[0208] Step 1: Benzyl 4-[2-(tert-butoxycarbonylamino)ethoxy]piperazine-1-carboxylate A solution of benzyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.13 mmol) in DMF (10 mL) was added with sodium hydride (170 mg, 4.25 mmol) portionwise at 0 °C. The reaction mixture was stirred for 30 minutes and then tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (474 mg, 2.13 mmol) was added. The reaction was slowly warmed to room temperature and stirred overnight. The reaction mixture was washed with brine and extracted into DCM. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give benzyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)piperidine-1-carboxylate (760 mg, yield 94.5%). MS (ESI, m / z): 379.2 [M+H] + .

[0209] Step 2: tert-Butyl N-[2-(4-piperidyloxy)ethyl]carbamate To a solution of benzyl 4-(2-((tert-butoxycarbonyl)amino)ethoxy)piperidine-1-carboxylate (760 mg, 2.01 mmol) in EtOH (20 mL) was added Pd(OH)2 (300 mg), and the reaction was stirred at room temperature for 6 hours under a hydrogen atmosphere. The mixture was filtered and the filtrate was concentrated in vacuo to give tert-butyl (2-(piperidin-4-yloxy)ethyl)carbamate (320 mg, yield 65.2%). MS (ESI, m / z): 245.1 [M+H] + .

[0210] Type VII Intermediate: 403 tert-Butyl 3-(4-piperidyloxymethyl)azetidine-1-carboxylate

Chemical Structure

[0211] Step 1: tert-Butyl 3-(4-pyridyloxymethyl)azetidine-1-carboxylate A solution of tert-butyl 3-(hydroxymethyl)azetidine-1-carboxylate (500 mg, 2.67 mmol) in DMF (10 mL) was added sodium hydride (320 mg, 8.01 mmol) portionwise at 0 °C. The reaction mixture was stirred for 30 minutes and then 4-fluoropyridine hydrochloride (357 mg, 2.67 mmol) was added. The reaction mixture was slowly warmed to 60 °C and stirred for 1 hour. The reaction was quenched with water and extracted with EtOAc. The organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give tert-butyl 3-((pyridin-4-yloxy)methyl)azetidine-1-carboxylate (600 mg, 85% yield). MS (ESI, m / z): 265.1 [M+H] + .

[0212] Step 2: tert-butyl 3-[(1-benzylpyridin-1-ium-4-yl)oxymethyl]azetidine-1-carboxylate; chloride To a solution of tert-butyl 3-((pyridin-4-yloxy)methyl)azetidine-1-carboxylate (600 mg, 2.27 mmol) in MeCN (10 mL) was added (chloromethyl)benzene (287 mg, 2.27 mmol). The reaction was stirred at 70 °C for 15 hours. The reaction mixture was cooled to room temperature and concentrated in vacuo to give 1-benzyl-4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)pyridin-1-ium chloride (882 mg, 99.4% yield). MS (ESI, m / z): 355.2 [M] + .

[0213] Step 3: tert-butyl 3-[(1-benzyl-3,6-dihydro-2H-pyridin-4-yl)oxymethyl]azetidine-1-carboxylate A solution of 1-benzyl-4-((1-(tert-butoxycarbonyl)azetidin-3-yl)methoxy)pyridin-1-ium chloride (800 mg, 2.05 mmol) in MeOH (15 mL) cooled in an ice bath was added sodium borohydride (387 mg, 10.2 mmol) portionwise in several times. The reaction mixture was slowly warmed to room temperature and stirred overnight. The reaction was quenched with ammonium chloride and washed with brine. The mixture was extracted with EtOAc, the organic layer was dried over anhydrous Na2SO4 and concentrated in vacuo to give tert-butyl 3-(((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)methyl)azetidine-1-carboxylate (700 mg, yield 95.4%). MS (ESI, m / z): 359.2 [M+H] + .

[0214] Step 4: tert-Butyl 3-(4-piperidyloxymethyl)azetidine-1-carboxylate To a solution of tert-butyl 3-(((1-benzyl-1,2,3,6-tetrahydropyridin-4-yl)oxy)methyl)azetidine-1-carboxylate (700 mg, 1.95 mmol) in EtOH (20 mL) was added Pd(OH)2 (350 mg), and the reaction mixture was stirred at room temperature for 2 h under a hydrogen atmosphere. The reaction mixture was filtered through a filter, and the filtrate was concentrated in vacuo to give tert-butyl 3-((piperidin-4-yloxy)methyl)azetidine-1-carboxylate (430 mg, yield 81.4%). MS (ESI, m / z): 271.2 [M+H] + .

[0215] Type VII Intermediate: 404 tert-Butyl (2-(azetidin-3-yloxy)ethyl)carbamate

Chemical Structure

[0216] Step 1: Benzyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azetidine-1-carboxylate In a 100 mL round-bottom flask, NaH (255 mg, 6.37 mmol) was combined with DMF (15 mL) to obtain a colorless solution. Benzyl 3-hydroxyazetidine-1-carboxylate (1.1 g, 5.31 mmol) was added at 0 °C. The reaction mixture was stirred at 0 °C for 30 minutes, and then the reaction mixture was stirred at room temperature for 30 minutes. Then, tert-butyl 1,2,3-oxathiazolidine-3-carboxylate 2,2-dioxide (1.42 g, 6.37 mmol) was added at 0 °C. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL of H2O and extracted with EtOAc (3 × 50 mL). The organic layers were combined and washed with saturated NaCl (1 × 50 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to obtain benzyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azetidine-1-carboxylate (1.86 g, yield 100%).

[0217] Step 2: tert-butyl (2-(azetidin-3-yloxy)ethyl)carbamate In a 100 mL round-bottom flask, benzyl 3-(2-((tert-butoxycarbonyl)amino)ethoxy)azetidine-1-carboxylate (350 mg, 999 μmol) was combined with MeOH (30 mL) to obtain a colorless solution. Pd-C (21.3 mg, 200 μmol) was added. The reaction mixture was purged with hydrogen three times and then stirred at room temperature for 1 hour. The reaction mixture was filtered through Celite. The filtrate was concentrated in vacuo to obtain tert-butyl (2-(azetidin-3-yloxy)ethyl)carbamate (122 mg, yield 56.5%). (ESI, m / z): 217.3 [M+H]+.

[0218] Type VII Intermediate: 405 tert-butyl (R)-(1-(piperazine-1-carbonyl)pyrrolidin-3-yl)carbamate

Chemical Structure

[0219] Project 1: Benzyl (R)-4-(3-((tert-butoxycarbonyl)amino)pyrrolidine-1-carbonyl)piperazine-1-carboxylate (R)-3-(Boc-amino)pyrrolidine (0.5 g, 2.68 mmol), 1-Cbz-piperazine (0.59 g, 2.68 mmol), triphosgene (0.48 g, 0.810 mmol) and triethylamine (0.93 mL, 6.71 mmol) in DMF (15 mL) were stirred at 25 °C for 16 h. The mixture was quenched with water (50 mL) and extracted with ethyl acetate (20 mL×3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was then purified by flash column chromatography to give the title compound (178 mg) as a white solid. MS (ESI, m / z): 433.2 [M+H] + .

[0220] Project 2: tert-Butyl (R)-(1-(piperazine-1-carbonyl)pyrrolidin-3-yl)carbamate A solution of benzyl 4-[3-(tert-butoxycarbonylamino)pyrrolidine-1-carbonyl]piperazine-1-carboxylate (148.0 mg, 0.340 mmol) and Pd / C (20.0 mg, 15% w / w) in methanol (10 mL) was stirred at 25 °C for 6 h under a hydrogen atmosphere. After filtering through celite, the filtrate was concentrated under reduced pressure to give the title compound (100 mg) as a white solid, which was used in the next step without purification. MS (ESI, m / z): 299.2 [M+H] + .

[0221] VII Intermediate: 406 tert-Butyl 4-(4-piperidylsulfonyl)piperazine-1-carboxylate

Chemical formula

[0222] Project 1: tert-Butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)sulfonyl]piperazine-1-carboxylate A mixture of N,N-diisopropylethylamine (0.69 mL, 3.93 mmol), 1-Boc-piperazine (439.56 mg, 2.36 mmol), and benzyl 4-chlorosulfonylpiperidine-1-carboxylate (0.5 g, 1.57 mmol) in DCM (10 mL) was stirred at 25 °C for 3 h under nitrogen. Water (5 mL) was added to the mixture, and this was extracted with DCM (10 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was then purified by flash column to afford the title compound (570 mg) as a white solid. MS (ESI, m / z): 490.2 [M+H] + .

[0223] Project 2: tert-Butyl 4-(4-piperidylsulfonyl)piperazine-1-carboxylate A solution of Pd / C (100.0 mg, 18% w / w) and tert-butyl 4-[(1-benzyloxycarbonyl-4-piperidyl)sulfonyl]piperazine-1-carboxylate (570 mg, 1.22 mmol) in methanol (20 mL) was stirred at 25 °C for 12 h under a hydrogen atmosphere. After filtration, the filtrate was concentrated under reduced pressure to afford the title compound (455 mg) as a colorless oil. MS (ESI, m / z): 334.2 [M+H] + .

[0224] The following type VII intermediates were prepared in the same manner as 406:

Table 10

[0225] Type VII intermediate: 409 Methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propanoate (409) and 3-methoxy-1-(piperazin-1-yl)propan-1-one (409a)

Chem.

[0226] Step 1: Benzyl 4-(3-hydroxypropanoyl)piperazine-1-carboxylate A mixture of 1-Cbz-piperazine (5.0 g, 22.7 mmol), 3-hydroxypropionic acid (3.07 g, 34.05 mmol), 1-propylphosphonic anhydride solution, 50 wt% in ethyl acetate (28.89 g, 45.4 mmol) and N,N-diisopropylethylamine (9.88 mL, 56.75 mmol) in DCM (113.5 mL) was stirred at 25 °C for 16 h. The mixture was added to water (20 mL) and extracted with ethyl acetate (20 mL × 3). The combined organic layers were concentrated under reduced pressure. The residue was purified by column to give the title compound (2.91 g) as a brown oil. MS(ESI, m / z): 293.1 [M+H] + .

[0227] Step 2: Benzyl 4-[3-(3-methoxy-3-oxo-propoxy)propanoyl]piperazine-1-carboxylate and benzyl 4-(3-methoxypropanoyl)piperazine-1-carboxylate Methyl acrylate (0.93 mL, 10.26 mmol) was added to a mixture of benzyl 4-(3-hydroxypropanoyl)piperazine-1-carboxylate (2.5 g, 8.55 mmol) and sodium methoxide (1386.01 mg, 25.66 mmol) in THF (42.76 mL). The mixture was stirred at 25 °C for 12 h. The mixture was quenched with water (10 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were concentrated under reduced pressure. The crude product was then purified by flash column chromatography to give a mixture of the title compounds (732 mg) as a yellow oil.

[0228] Step 3: Methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propanoate and 3-methoxy-1-(piperazin-1-yl)propan-1-one Benzyl 4-[3-(3-methoxy-3-oxo-propoxy)propanoyl]piperazine-1-carboxylate and benzyl 4-(3-methoxypropanoyl)piperazine-1-carboxylate (732 mg) and a mixture of Pd / C (73 mg, 10% w / w) in methanol (20 mL) were stirred under a hydrogen atmosphere for 48 hours. The mixture was filtered through Celite, and the filtrate was concentrated under reduced pressure to give a mixture of the title compounds (476 mg) as a brown gum.

[0229] VII Intermediate: 410 3-Cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole [Chemical formula]

[0230] Step 1: tert-Butyl 4-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylate To a solution of (Z)-N'-hydroxycyclobutanecarboximidamide (4.68 g, 41 mmol, 0.99 eq) in DMF (70 mL) and pyridine (6.85 g, 7 mL, 86.5 mmol, 2.09 eq) at 50 °C was added dropwise over 30 minutes a solution of 2-(1-(tert-butoxycarbonyl)piperidin-4-yl)acetic acid (isopropyl carbonate) anhydride (13.64 g, 41.4 mmol) in DMF (7 mL). The mixture was then stirred at the same temperature for 1 hour. The pale yellow clear solution was then heated to 100 °C and stirred overnight. The mixture was evaporated, adsorbed on an Isolute® HM-N column, dried, and purified by flash chromatography to give tert-butyl 4-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylate (8.866 g, 27.5 mmol, 66.6% yield) as a colorless oil. MS (ESI, m / z): 266.2 [M-tBu+H] + .

[0231] Step 2: 3-Cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole To a solution of tert-butyl 4-((3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl)piperidine-1-carboxylate (27.55 g, 85.7 mmol, 1 equiv) in dichloromethane (240 mL) was added 4 M HCl in dioxane (85 mL, 340 mmol) dropwise over 1.5 h, and the mixture was stirred at room temperature for 2.5 h and then evaporated. Evaporation was stopped when the product began to crystallize, 300 mL of diethyl ether was added, and the mixture was stirred at room temperature for 30 min. The white crystals were filtered off, washed twice with 100 mL of diethyl ether, and dried under reduced pressure to give 3-cyclobutyl-5-(piperidin-4-ylmethyl)-1,2,4-oxadiazole (21.618 g, 83.9 mmol, 97.8% yield) as white crystals. MS(ESI, m / z): 222.2 [M+H] + .

[0232] Type VIII Intermediate: 411 tert-Butyl (2-amino-2-oxoethyl)(2-(piperazin-1-yl)ethyl)carbamate

Chemical Structure

[0233] Step 1: Benzyl 4-(2-(1,3-dioxoisoindolin-2-yl)ethyl)piperazine-1-carboxylate A mixture of N-(2-bromoethyl)phthalimide (5.0 g, 19.68 mmol), 1-Cbz-piperazine (5.2 g, 23.61 mmol), and triethylamine (4.11 mL, 29.52 mmol) in THF (30 mL) was stirred at 70 °C for 14 h. H2O (100 mL) was added to the mixture, and this was extracted with ethyl acetate (50 mL×3). The combined organic layers were dried over sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography to give the title compound (4.29 g) as a brown oil. MS(ESI, m / z): 394.2[M+H] + .

[0234] Step 2: Benzyl 4-(2-aminoethyl)piperazine-1-carboxylate A mixture of benzyl 4-[2-(1,3-dioxoisoindolin-2-yl)ethyl]piperazine-1-carboxylate (4.26 g, 10.83 mmol) and hydrazine hydrate (1.28 g, 21.7 mmol) in ethanol (50 mL) was stirred at 80 °C for 2 h. The mixture was filtered through a filter, and the filtrate was concentrated under reduced pressure to obtain the title compound (2.78 g) as a white solid, which was used in the next step without further purification. MS (ESI, m / z): 264.2 [M+H] + .

[0235] Step 3: Benzyl 4-(2-((2-amino-2-oxoethyl)(tert-butoxycarbonyl)amino)ethyl)piperazine-1-carboxylate trifluoroacetate

[0236] To a mixture of benzyl 4-(2-aminoethyl)piperazine-1-carboxylate (1.5 g, 5.7 mmol) and N,N-diisopropylethylamine (4.96 mL, 28.48 mmol) in tetrahydrofuran (20 mL) was added 2-bromoacetamide (0.79 g, 5.7 mmol). The mixture was stirred at 25 °C for 14 h. Di-tert-butyl dicarbonate (2.49 g, 11.39 mmol) was added to the mixture. The mixture was stirred at 25 °C for 14 h. Water (30 mL) was added to the mixture, and the mixture was extracted with ethyl acetate (20 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO3 (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100×21.2 mm 5 μm; 5% - 95% ACN in H2O containing 0.1% TFA as the eluent) to obtain the title compound (237 mg) as a white solid. MS (ESI, m / z): 421.2 [M+H] + .

[0237] Step 4: tert-Butyl (2-amino-2-oxoethyl)(2-(piperazin-1-yl)ethyl)carbamate A mixture of benzyl 4-[2-[(2-amino-2-oxo-ethyl)-tert-butoxycarbonyl-amino]ethyl]piperazine-1-carboxylate trifluoroacetate (237.0 mg, 0.560 mmol) and Pd / C (47.4 mg, 20% w / w) in methanol (10 mL) was stirred at 25 °C for 14 h. The mixture was filtered through celite and the filtrate was concentrated under reduced pressure to afford the title compound (122 mg) as a brown gum. MS (ESI, m / z): 287.2 [M+H] + .

[0238] The following type VIII intermediates were prepared in the same manner as 411: [Table 11]

[0239] Type IX intermediate: 413 N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide [Chemical Structure]

[0240] The title compound was obtained from N-[3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (intermediate 374) and 1-(tert-butoxycarbonyl)piperidine-4-carboxylic acid in the same manner as in Steps 1-2 of Example 11. MS (ESI, m / z): 601.3 [M+H] +

[0241] Type X intermediate: 415 2-(3-tert-Butoxycarbonylazetidin-1-yl)acetic acid [Chemical]

[0242] Step 1: tert-Butyl 1-(2-benzyloxy-2-oxo-ethyl)azetidine-3-carboxylate

[0243] To a solution of tert-butyl azetidine-3-carboxylate hydrochloride (910 mg, 4.7 mmol) and N,N-diisopropylethylamine (2.05 mL, 11.75 mmol) in DCM (15 mL) was added benzyl 2-bromoacetate (1.4 g, 6.11 mmol). The mixture was stirred at 25 °C for 5 h. After removing the solvent in vacuo, the crude product was purified by column chromatography to afford the title compound (980 mg) as a colorless oil. MS (ESI, m / z): 306.2 [M+H] + .

[0244] Step 2: 2-(3-tert-Butoxycarbonylazetidin-1-yl)acetic acid To a solution of tert-butyl 1-(2-benzyloxy-2-oxo-ethyl)azetidine-3-carboxylate (900 mg, 2.95 mmol) in methanol (5 mL) was added Pd / C (50.0 mg, 6% w / w) under a nitrogen atmosphere. The mixture was stirred at 25 °C for 18 h under a hydrogen atmosphere. The mixture was filtered through Celite, and the filtrate was concentrated in vacuo to afford the title compound (660 mg) as a white solid. MS (ESI, m / z): 216.2 [M+H] + .

[0245] The following Intermediate X was prepared in the same manner as 415: [Table 12]

[0246] Intermediate XI: 394 tert-Butyl 4-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperazine-1-carboxylate

Chem.

[0247] At room temperature, a mixture of 4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoic acid (Intermediate 313, 5.2 g, 14.5 mmol), tert-butyl piperazine-1-carboxylate (3.24 g, 17.4 mmol), HATU (6.62 g, 17.4 mmol) and DIPEA (5.62 g, 7.6 mL, 43.5 mmol) in DMF (5 mL) was stirred for 2 hours. Then the mixture was poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried and concentrated to give the title compound (6.5 g, yield 85.1%) as a solid. MS (ESI, m / z): 526.1 [M+H] +

[0248] The following Type XI intermediates were prepared in the same manner as Intermediate 394.

Table 13

[0249] Type XI Intermediate: 418 5-Bromo-N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-1-methyl-imidazole-2-carboxamide

Chem.

[0250] At room temperature, 12N HCl (10 mL) was added to a suspension of tert-butyl 4-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperazine-1-carboxylate (Intermediate 394, 6.5 g, 12.3 mmol) in THF (50 mL). After stirring for 1 hour, the solution was basified with NH3·H2O. The aqueous phase was extracted with DCM. The organic layer was washed with water, dried, and concentrated to obtain the title compound (5 g, yield 95%) as a yellow solid. MS (ESI, m / z): 426.2 [M+H] +

[0251] The following Type XI intermediates were prepared in the same manner as Intermediate 418.

Table 14

[0252] Type XI intermediate: 420 1-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylic acid

Chemical formula

[0253] Step 1: Methyl 1-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylate A mixture of 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoic acid (Intermediate 313, 2.8 g, 7.81 mmol), methyl piperidine-4-carboxylate (1.34 g, 9.37 mmol), HATU (3.86 g, 10.2 mmol), and DIPEA (5.05 g, 6.82 mL, 39 mmol) in DMF (15 mL) was stirred at 25 °C overnight. The mixture was then poured into water. The aqueous phase was extracted with DCM. The organic phase was dried and concentrated to obtain the crude product (1.9 g, yield 50.3%) as a yellow oil. MS (ESI, m / z): 483.1 [M+H] +

[0254] Step 2: 1-[4-[(5-Bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carboxylic acid A solution of methyl 1-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperidine-4-carboxylate (1.9 g, 3.93 mmol) and lithium hydroxide monohydrate (824 mg, 19.6 mmol) in THF (24 mL), water (12 mL), and MeOH (1 mL) was stirred for 3 h. The solution was then concentrated, and the aqueous layer was acidified with CH3COOH. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried, and concentrated to give the title compound (1.6 g, 86.7% yield) as a yellow oil. MS (ESI, m / z): 469.2 [M+H] +

[0255] Type XII Intermediate: 421 tert-Butyl 3-[[[1-[4-[(5-bromo-1-methyl-imidazole-2-carbonyl)amino]-2-chloro-benzoyl]piperidine-4-carbonyl]amino]methyl]azetidine-1-carboxylate [Chemical Structure]

[0256] At room temperature, a mixture of 1-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamide)-2-chlorobenzoyl)piperidine-4-carboxylic acid (Intermediate 420, 1.6 g, 3.41 mmol), tert-butyl 3-(aminomethyl)azetidine-1-carboxylate (1.9 g, 10.2 mmol), DIPEA (1.32 g, 1.78 mL, 10.2 mmol) and HATU (1.94 g, 5.11 mmol) in DMF (15 mL) was stirred for 1 hour. Then, the mixture was poured into water and the aqueous phase was extracted with DCM. The organic phase was washed with water, dried and concentrated. The residue was purified by flash column to obtain the title compound (1.8 g, yield 82.8%) as a yellow oil. MS(ESI,m / z):637.2[M+H] +

[0257] The following type XII intermediates were prepared in the same manner as Intermediate 421:

Table 15-Ⅰ

Table 15-Ⅱ

[0258] Type XII intermediate: 431 5-bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide

Chemical formula

[0259] Route 1: At room temperature, 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (7.28 g, 22.9 mmol) was added to a mixture of 4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoic acid (Intermediate 313, 4.1 g, 11.4 mmol), N,N-dimethyl-2-(piperazin-1-yl)ethane-1-amine (2.7 g, 17.2 mmol) and DIPEA (4.43 g, 5.99 mL, 34.3 mmol) in DMF (10 mL). After stirring for 20 minutes, the reaction was completed. The mixture was poured into water. The aqueous phase was extracted with DCM. The organic phase was washed with water, dried and concentrated. The residue was dried by a freeze dryer to obtain the title compound (5.2 g, yield 91.4%) as a white solid. MS(ESI,m / z):496.8[M+H] +

[0260] Route 2: Step 1: (4-Amino-2-chloro-phenyl)-[4-[2-(dimethylamino)ethyl]piperazin-1-yl]methanone (Intermediate 433) To a solution of 1-(2-dimethylaminoethyl)piperazine (0.35 g, 2.24 mmol), 4-amino-2-chlorobenzoic acid (0.35 g, 2.04 mmol) and N,N-diisopropylethylamine (0.71 mL, 4.08 mmol) in DMF (10 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (0.93 g, 2.45 mmol). The mixture was stirred at 30 °C for 3 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (75 mL × 2). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to obtain the title compound (600 mg, 1.93 mmol, yield 94.63%) as a light brown oil. MS(ESI,m / z):311.1[M+H] + .

[0261] Project 2: 5-Bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (Intermediate 432) (4-Amino-2-chloro-phenyl)-[4-[2-(dimethylamino)ethyl]piperazine-1-yl]methanone (295.64 mg, 0.950 mmol), 5-bromo-1-methyl-imidazole-2-carboxylic acid (150 mg, 0.730 mmol) and N,N-diisopropylethylamine (0.23 mL, 1.33 mmol) in DMF (3 mL) were added O-(7-azabenzotriazol-1-yl)-N,N,N’,N’-tetramethyluronium hexafluorophosphate (303.49 mg, 0.800 mmol). The mixture was stirred at 30 °C for 3 hours. The mixture was diluted with water (60 mL) and extracted with EtOAc (75 mL x 2). The organic layer was washed with brine (50 mL x 2), dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give the title compound (70 mg, 0.140 mmol, 19.22% yield) as a light brown solid. MS (ESI, m / z): 499.0 [M+H] + .

[0262] Type XIII Intermediate:434 (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid and (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid

Chemical Structure

[0263] A solution of (2S)-1-tert-butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in THF (20 mL) was added dropwise to a solution of 1.5 M methyllithium in diethyl ether (8.72 mL, 13.09 mmol) at -20 °C under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 hour and then further stirred at 25 °C for 11 hours. Under ice-cooling, the reaction mixture was added to 1 N aqueous hydrochloric acid solution (50 mL), followed by extraction with ethyl acetate (50 mL x 3). The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (FA) to obtain two final compounds: P1, (2S,4R)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (50 mg, 0.200 mmol, 2.34% yield) as a dark green solid, MS (ESI, m / z): 190.0 [M + H - 56] + And compound P2, (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-methyl-pyrrolidine-2-carboxylic acid (600 mg, 2.45 mmol, 28.04% yield) was obtained as an off-white solid. MS (ESI, m / z): 190.0 [M + H - 56] + .

[0264] Type XIII intermediate: 436 (2S,4S)-1-tert-butoxycarbonyl-4-hydroxy-4-ethyl-pyrrolidine-2-carboxylic acid and (2S,4R)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid

Chemical formula

[0265] (2S)-1-tert-Butoxycarbonyl-4-oxo-pyrrolidine-2-carboxylic acid (2 g, 8.72 mmol) in THF (50 mL) was added dropwise with ethylmagnesium bromide (7.27 mL, 21.81 mmol, 3 M in diethyl ether) at -20 °C under a nitrogen atmosphere. The resulting mixture was stirred at the same temperature for 1 h and then further stirred at 25 °C for 10 h. Under ice-cooling, the reaction mixture was added to 1 N aqueous hydrochloric acid (100 mL) and then extracted with ethyl acetate. The organic layer was washed with brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure. The crude product was purified by preparative HPLC (FA) to give two final compounds: the title compound P1, (2S,4S)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.8 g, 3.09 mmol, 35.36% yield) as an off-white solid, MS (ESI, m / z): 282.0 [M+Na]+, and the title compound P2, (2S,4R)-1-tert-butoxycarbonyl-4-ethyl-4-hydroxy-pyrrolidine-2-carboxylic acid (0.2 g, 0.770 mmol, 8.84% yield) as an off-white solid. MS (ESI, m / z): 282.0 [M+Na] + .

[0266] Type XIII intermediate: 12 (3S,4R)-1-tert-Butoxycarbonyl-3-hydroxy-piperidine-4-carboxylic acid

Chem.

[0267] Step 1: (3S,4R)-1-tert-Butoxycarbonyl-3-hydroxy-piperidine-4-carboxylic acid (12) A solution of 1-(tert-butyl) 4-ethyl (3S,4R)-3-hydroxypiperidine-1,4-dicarboxylate (2.1 g, 7.68 mmol) in methanol (20 mL) / THF (20 mL) / water (20 mL) was added with lithium hydroxide (0.46 g, 19.21 mmol), and the reaction mixture was stirred at 30 °C for 12 hours. The crude product was adjusted to pH = 7 using 1N aqueous solution of HCl, and then the solution was lyophilized to obtain the title compound (2.4 g, 9.79 mmol, yield 76.42%) as an off-white solid. This was used without further purification. MS (ESI, m / z): 190.0 [M+H-56] + .

[0268] Intermediate 437 (3S,4S)-1-tert-butoxycarbonyl-3-hydroxy-piperidine-4-carboxylic acid (3S,4S)-1-tert-butoxycarbonyl-3-hydroxy-piperidine-4-carboxylic acid can be prepared in the same manner as Intermediate 12 using CAS [2166250-53-7].

[0269] Type I Example: 13 N-[4-(4-aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical Structure

[0270] The crude N-[4-(4-aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (Intermediate 373, 200 mg) was purified by preparative HPLC to obtain the title compound (50 mg). MS (ESI, m / z): 504.2 [M+H] +

[0271] The following Type I Examples were prepared in the same manner as Example 13.

Table 16

[0272] Type I Example: 17 N-[4-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical formula

[0273] Step 1 N-[3-Chloro-4-[4-[2-(methylamino)ethyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide In a 100 mL round-bottom flask, 2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoic acid (200 mg, 474 μmol), tert-butyl (2-(piperidin-4-yl)ethyl)carbamate (141 mg, 616 μmol) and DIPEA (184 mg, 248 μL, 1.42 mmol) were combined with DMF to obtain a light brown solution. 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (603 mg, 948 μmol) was added. The reaction mixture was stirred at room temperature overnight. The reaction mixture was poured into 50 mL of H2O and extracted with EtOAc (3 × 25 mL). The organic layers were combined and washed with saturated NaCl (3 × 25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl (2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperidin-4-yl)ethyl)carbamate (295 mg, yield 98.4%). MS (ESI, m / z): 632.1 [M+H]+.

[0274] Step 2 N-[4-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate In a 100 mL round-bottom flask, tert-butyl (2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperidin-4-yl)ethyl)carbamate (295 mg, 467 μmol) was combined with THF (3 mL) to obtain a pale yellow solution. 4M HCl in dioxane (3.5 mL, 14 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-[4-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-chlorophenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide formate (270 mg, yield 98.1%). MS (ESI, m / z): 532.2 [M+H]+.

[0275] The following type II and type III examples were prepared in the same manner as Example 17.

Table 17-1

Table 17-2

[0276] Type II example: 28 N-[(1S)-2-Amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide trifluoroacetate

Chemical formula

[0277] Process 1: tert-Butyl N-[(2S)-2-[[1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propyl]carbamate At room temperature, 2,4,6-Tripropyl-1,3,5,2,4,6-trioxatriphosphinan 2,4,6-trioxide (358 mg, 1.13 mmol) was added to a mixture of 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxylic acid (Intermediate 362, 300 mg, 563 μmol), tert-Butyl (S)-(2-aminopropyl)carbamate (98.1 mg, 563 μmol) and DIPEA (218 mg, 295 μl, 1.69 mmol) in DMF (2 mL). After stirring for 1 hour, the mixture was poured into water. The aqueous phase was extracted with DCM. The combined organic phases were concentrated and the residue was used in the next step reaction without further purification. MS(ESI,m / z):689.1[M+H] +

[0278] Process 2: N-[(1S)-2-Amino-1-methylethyl]-1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 2,2,2-Trifluoroacetic acid At room temperature, a solution of tert-butyl (S)-(2-(1-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperidine-4-carboxamido)propyl)carbamate from Step 1 in TFA (5 mL) and CH2Cl2 (5 mL) was stirred for 2 hours. The mixture was then filtered. Water (10 mL) was added. The mixture was basified to pH 8 - 9 with NH3·H2O. The aqueous phase was extracted with DCM. The organic phase was dried over anhydrous Na2SO4 and concentrated. The residue was purified by preparative HPLC to give the title compound (61 mg). MS (ESI, m / z): 589.4 [M+H] +

[0279] The following Type II or Type III examples were prepared in the same manner as Example 28, and the deprotection step 2 was applied only to the intermediate obtained from the Boc-protected amine.

Table 18-1

Table 18-2

Table 18-3

Table 18-4

Table 18-5

Table 18-6

Table 18-7

Table 18-8

Table 18-9

Table 18-10

Table 18-11

Table 18-12

Table 18-13

Table 18-14

Table 18-15

Table 18-16

[0280] Type II Example: 11 N-[3-chloro-4-[4-[(2-pyrrolidin-3-ylacetyl)amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical formula

[0281] Step 1: tert-butyl 3-[2-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]amino]-2-oxo-ethyl]pyrrolidine-1-carboxylate N-[4-(4-Aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide (Intermediate 373, 200 mg, 397 μmol), 2-(1-(tert-Butoxycarbonyl)pyrrolidin-3-yl)acetic acid (182 mg, 794 μmol), HATU (226 mg, 595 μmol) and DIPEA (154 mg, 208 μl, 1.19 mmol) in DMF (5 mL) were stirred overnight. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated to give the crude product (200 mg), which was used directly in the reaction of the next step. MS (ESI, m / z): 715.1 [M+H] +

[0282] Step 2: N-[3-Chloro-4-[4-[(2-Pyrrolidin-3-ylacetyl)amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; Formic acid At room temperature, a mixture of 3-[2-[[1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]amino]-2-oxo-ethyl]pyrrolidine-1-carboxylate (200 mg, 280 μmol) in DCM (2 mL) and TFA (3 mL) was stirred for 1 hour. Under ice-cooling, Et3N was added dropwise with stirring until pH 8 - 9. Then, water (10 mL) was added. The aqueous layer was extracted with DCM. The organic layer was concentrated to give the crude product, which was purified by preparative HPLC to give the title compound (62 mg). MS (ESI, m / z): 615.1 [M+H] +

[0283] The following Type II or Type III examples were prepared in the same manner as Example 11.

Table 19-1

Table 19-2

Table 19-3

Table 19-4

Table 19-5

Table 19-6

Table 19-7

Table 19-8

Table 19-9

Table 19-10

Table 19-11

Table 19-12

Table 19-13

Table 19-14

Table 19-15

Table 19-16

Table 19-17

Table 19-18

Table 19-19

Table 19-20

Table 19-21

Table 19-22

Table 19-23

Table 19-24

Table 19-25

Table 19-26

Table 19-27

Table 19-28

Table 19-29

[0284] Type II Example: 235 N-[3-chloro-4-[4-(4-piperidylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical Structure

[0285] Project 1: tert-Butyl 4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-4-piperidyl]sulfamoyl]piperidine-1-carboxylate A mixture of N-[4-(4-aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide (Intermediate 373, 300 mg, 595 μmol), tert-butyl 4-(chlorosulfonyl)piperidine-1-carboxylate (253 mg, 893 μmol), and Et3N (120 mg, 166 μmol, 1.19 mmol) in DCM (5 mL) was stirred overnight. Then, the clear solution was washed with water, dried over anhydrous Na2SO4, and concentrated to give the title compound (300 mg) as a brown solid, which was used in the next step reaction without further purification. MS (ESI, m / z): 750.8 [M+H] +

[0286] Project 2: N-[3-Chloro-4-[4-(4-piperidylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; Formic acid tert-Butyl 4-(N-(1-(2-chloro-4-(5-(2,3-difluoromethoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperidin-4-yl)sulfamoyl)piperidine-1-carboxylate (300 mg, 399 μmol) was dissolved in DCM (5 mL) and TFA (5 mL). The solution was stirred for 2 hours. Under ice-cooling, water (5 mL) was added, followed by the addition of Et3N until pH 8 - 9 was reached. The aqueous layer was extracted with DCM. The organic layer was concentrated to obtain a crude product, which was purified by preparative HPLC to give the title compound (126 mg). MS (ESI, m / z): 651.0 [M+H] +

[0287] The following Type II and Type III examples were prepared in the same manner as Example 235.

Table 20-1

Table 20-2

[0288] Type II Example: 243 N-[3-Chloro-4-[4-[3-(methylamino)propanoyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Chemical Structure

[0289] A mixture of N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide (Intermediate 374, 250 mg, 510 μmol), 2-chloro-N-methylethan-1-amine (57.3 mg, 612 μmol), and sodium iodide (76.5 mg, 510 μmol), K2CO3 (141 mg, 1.02 mmol) in DMF (2 mL) was stirred at 85 °C for 3 hours. The mixture was then poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water and concentrated. The residue was purified by preparative HPLC to give the title compound (42 mg). MS (ESI, m / z): 547.2 [M+H] +

[0290] The following Type II examples were prepared in the same manner as Example 243.

Table 21

[0291] Type II Example: 245 N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide trifluoroacetate

Chem.

[0292] Step 1: tert-Butyl 3-[[[1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]methyl]azetidine-1-carboxylate A mixture of tert-butyl 3-((1-(4-(5-bromo-1-methyl-1H-imidazole-2-carboxamido)-2-chlorobenzoyl)piperidine-4-carboxamido)methyl)azetidine-1-carboxylate (Intermediate 421, 530 mg, 831 μmol), 2-(4-(difluoromethoxy)-2,3-difluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (Intermediate 315, 305 mg, 997 μmol), Na2CO3 (440 mg, 4.15 mmol) and 1,1′-bis(di-tert-butylphosphino)ferrocene palladium dichloride (54.1 mg, 83.1 μmol) in 1,4-dioxane (15 mL) and water (1.5 mL) was irradiated under microwave at 100 °C for 50 minutes. Then the mixture was concentrated and the residue was purified by flash column to give the title compound (400 mg, yield 65.3%) as a black oil. MS (ESI, m / z): 737.8 [M+H] +

[0293] Step 2: N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 2,2,2-trifluoroacetic acid At room temperature, CF3COOH (6 mL) was added to a solution of tert-butyl 3-[[[1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluorophenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]methyl]azetidine-1-carboxylate (400 mg, 543 μmol) in DCM (10 mL). The solution was stirred for 40 minutes. Under ice-cooling, NH3·H2O was added until pH 8-9 was reached. The solution was concentrated, and the aqueous layer was extracted with DCM. The organic layer was concentrated to obtain a crude product, which was purified by preparative HPLC to give the title compound (21 mg). MS (ESI, m / z): 637.3 [M+H] +

[0294] The following Type II examples were prepared in the same manner as Example 245.

Table 22-1

Table 22-2

Table 22-3

Table 22-4

Table 22-5

[0295] Type II Example: 269 5-[3-chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamidotrifluoroacetate

Chemical formula

[0296] 5-Bromo-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide (Intermediate 431, 200 mg, 402 μmol), 2-[2-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy]acetonitrile (Intermediate 325, 118 mg, 402 μmol), Na2CO 3( 128 mg, 1.21 mmol) and a mixture of 1,1'-bis(di-tert-butylphosphino)ferrocene palladium dichloride (26.2 mg, 40.2 μmol) in 1,4-dioxane (4 mL) and water (0.4 mL) was irradiated under microwave at 100 °C for 1 h. The mixture was filtered and concentrated. Water was added and the aqueous layer was extracted with DCM. The organic layer was concentrated and the crude product was purified by preparative HPLC to give the desired product (29 mg) as a light brown powder. MS (ESI, m / z): 584.3 [M+H] +

[0297] The following Type II examples were prepared in the same manner as Example 269:

Table 23-1

Table 23-2

[0298] Type II Example: 279 N-(4-(4-(3-(3-Amino-3-oxopropoxy)propanoyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide

Chemical formula

[0299] Project 1: N-[3-chloro-4-[4-(3-methoxypropanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide 2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoic acid (500.0 mg, 0.950 mmol), methyl 3-(3-oxo-3-piperazin-1-yl-propoxy)propanoate and 3-methoxy-1-(piperazin-1-yl)propan-1-one (467 mg), N,N-diisopropylethylamine (0.41 mL, 2.37 mmol) and 1-propylphosphonic anhydride solution, a mixture in DMF (6 mL) in 50 wt% ethyl acetate (1207 mg, 1.9 mmol) was stirred at 25 °C for 16 h. The mixture was added to water (15 mL) and extracted with ethyl acetate (10 mL × 3). The combined organic layers were washed with saturated aqueous NaHCO3 (15 mL), dried over anhydrous Na2SO4 and concentrated under reduced pressure to give the crude product (637 mg) as a brown gum. 200 mg of the crude product was subjected to preparative HPLC (chromatography column: Kromasil-C18 100 × 21.2 mm 5 μm; 5% - 95% ACN in H2O containing 0.1% FA as eluent). The desired fraction was dried by lyophilization to give the final compound methyl 3-[3-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-3-oxopropoxy]propanoate (22 mg) as a white solid. MS (ESI, m / z): 576.2 [M+H] + ;

[0300] Project 2: N-(4-(4-(3-(3-amino-3-oxopropoxy)propanoyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide Methyl 3-[3-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-3-oxopropoxy]propanoate (220 mg, 0.34 mmol) and ammonia (5.0 mL, 0.340 mmol) were stirred at 40 °C for 12 h. The mixture was added to water (100 mL) and extracted with ethyl acetate (50 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated under reduced pressure. The mixture was purified by preparative HPLC (chromatography column: Kromasil-C 18 100×21.2 mm 5μm; eluent: 5% - 95% ACN in H2O containing 0.1% FA) to obtain the title compound (61.2 mg) as a white solid. MS(ESI, m / z): 633.2 [M+H] + .

[0301] The following Type II examples were prepared in the same manner as Example 279.

Table 24

[0302] Type III Example: 281 N-(2-aminoethyl)-4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamide 2,2,2-trifluoroacetate

Chemical formula

[0303] Step 1: tert-Butyl (2-(4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carboxamido)ethyl)carbamate A solution of triethylamine (0.06 mL, 0.400 mmol), N-Boc-ethylenediamine (64.68 mg, 0.400 mmol) and triethylamine (0.06 mL, 0.400 mmol) in DMF (1.45 mL) was stirred at 25 °C for 1 h, and a solution of N-[3-chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1H-imidazole-2-carboxamide; 2,2,2-trifluoroacetic acid (124.13 mg, 0.200 mmol) in DMF (2 mL) was added. The reaction was quenched with water (20 mL) and the resulting solution was extracted with ethyl acetate (20 mL × 3). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo to give the title compound (150 mg) as a light brown solid. MS(ESI, m / z): 701.2 [M+H] + .

[0304] Step 2: N-(2-aminoethyl)-4-(2-chloro-4-(5-(4-(cyanomethoxy)-2,3-difluorophenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carboxamide 2,2,2-trifluoroacetate A solution of tert-butyl N-[2-[[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl] amino] benzoyl]piperazine-1-carbonyl]amino]ethyl]carbamate (150 mg, 0.110 mmol) and trifluoroacetic acid (1.0 mL, 12.98 mmol) in DCM (5 mL) was stirred at 25 °C for 1 h. After concentration in vacuo, the residue was purified by preparative HPLC (chromatography column: Kromasil-C18 100×21.2mm 5μm; 5% - 95% ACN in H2O containing 0.1% TFA as eluent) to give the title compound (17 mg) as a white solid. MS(ESI, m / z): 601.2 [M+H] + .

[0305] The following Example III was prepared in the same manner as 281. [Table 25-1] [Table 25-2]

[0306] Example III: 288 2-[4-[4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetic acid trifluoroacetate [Chemical formula]

[0307] Step 1: Methyl 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetate

[0308] A mixture of N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methylimidazole-2-carboxamide (Intermediate 413, 400 mg, 666 μmol), methyl 2-bromoacetate (122 mg, 799 μmol) and Et3N (337 mg, 464 μl, 3.33 mmol) in acetonitrile (10 mL) was stirred at 85 °C for 2 hours and then concentrated. Water (5 mL) was added. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried over anhydrous Na2SO4 and concentrated. The residue (400 mg) was used in the next step without further purification. MS (ESI, m / z): 673.3 [M+H] +

[0309] Step 2: 2-[4-[4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetic acid trifluoroacetate To a solution of methyl 2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetate (400 mg, 594 μmol) in THF (24 mL), MeOH (1 mL) and water (12 mL) was added a solution of lithium hydroxide monohydrate (125 mg, 2.97 mmol). The mixture was stirred at room temperature overnight. The mixture was then concentrated and acidified with HCl to pH 3 - 4. The aqueous layer was extracted with a 1:6 iPrOH:DCM mixture. The organic layer was concentrated and the residue was purified by preparative HPLC to afford the title compound (30 mg) as a white powder. MS (ESI, m / z): 659.3 [M+H] +

[0310] The following Type III Examples were prepared in the same manner as Example 288.

Table 26

[0311] Type III Example: 290 N-[4-[4-[1-(2-Aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical Structure

[0312] Project 1: tert-Butyl N-[2-[4-[4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]ethyl]carbamate In a 100 mL round-bottom flask, N-(3-chloro-4-(4-(piperidine-4-carbonyl)piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide (55 mg, 91.5 μmol), tert-butyl (2-oxoethyl)carbamate (58.3 mg, 366 μmol) and sodium cyanoborohydride (28.8 mg, 458 μmol) were combined with MeOH (5 mL) to obtain a colorless solution. The reaction mixture was heated to 40 °C and stirred for 1 hour. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 25 mL of saturated NaHCO3 and extracted with EtOAc (3 × 25 mL). The organic layer was dried over Na2SO4 and concentrated in vacuo to give tert-butyl (2-(4-(4-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)ethyl)carbamate (68 mg, yield 8%). MS (ESI, m / z): 744.2 [M+H] +

[0313] Project 2: N-[4-[4-[1-(2-aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate In a 100 mL round-bottom flask, tert-butyl (2-(4-(4-(2-chloro-4-(5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamido)benzoyl)piperazine-1-carbonyl)piperidin-1-yl)ethyl)carbamate (68 mg, 91.4 μmol) was combined with THF (3 mL) to obtain a colorless solution. HCl (1.14 mL, 4.57 mmol) in dioxane was added. The reaction mixture was stirred at room temperature for 30 minutes, and the crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-(4-(4-(1-(2-aminoethyl)piperidine-4-carbonyl)piperazine-1-carbonyl)-3-chlorophenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide formate (19 mg, yield 29.5%). MS (ESI, m / z): 644.3 [M+H] +

[0314] The following Type III examples were prepared in the same manner as Example 290.

Table 27

[0315] Type III Example: 293 N-[3-chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate

Chemical formula

[0316] Intermediate 447 in Step 1: N-(3-chloro-4-(4-(2-chloroacetyl)piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide In a 100 mL round-bottom flask, N-(3-chloro-4-(piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide (500 mg, 1.02 mmol) and DIPEA (264 mg, 357 μL, 2.04 mmol) were combined with CH2Cl2 (20 mL) to obtain a light brown solution. 2-Chloroacetyl chloride (138 mg, 1.22 mmol) was added. The reaction mixture was stirred at room temperature for 20 minutes. The crude reaction mixture was concentrated in vacuo. The reaction mixture was poured into 50 mL of H2O and extracted with DCM (3 × 25 mL). The organic layers were combined, washed with saturated NaCl (1 × 50 mL), and the crude reaction mixture was concentrated in vacuo to obtain N-(3-chloro-4-(4-(2-chloroacetyl)piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide (530 mg, 936 μmol, 91.7% yield), which was used directly in the next step. (ESI, m / z): 566.0 [M+H]+.

[0317] Step 2 N-[3-chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine- carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide formate To a 5 mL microwave vial, N-(3-chloro-4-(4-(2-chloroacetyl)piperazine-1-carbonyl)phenyl)-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-1H-imidazole-2-carboxamide (75 mg, 132 μmol), pyrrolidine (47.1 mg, 662 μmol), DIEA (17.1 mg, 23.1 μl, 132 μmol) and sodium iodide (3.97 mg, 26.5 μmol) in acetonitrile (3 mL) were added. The vial was capped and heated at 80 °C for 30 minutes in a microwave. The crude reaction mixture was concentrated in vacuo. The crude material was purified by preparative HPLC to give N-[3-chloro-4-[4-(2-pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate (19 mg, yield 21.7%). (ESI, m / z): 601.3 [M+H]+.

[0318] The following type III examples were prepared in the same manner as Example 293:

Table 28

[0319] Type III Example: 299 N-[3-chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propanoyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide

Chemical Structure

[0320] N-[4-[4-[3-(2-aminoethoxy)propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide formate (246, 90 mg, 138 μmol), dimethylglycine (28.5 mg, 276 μmol), HATU (233 mg, 612 μmol) and DIPEA (158 mg, 214 μl, 1.22 mmol) in DMF (5 mL) were stirred overnight. The mixture was poured into water. The aqueous layer was extracted with DCM. The organic layer was washed with water, dried and concentrated. The residue was purified by preparative HPLC to give the title compound (29 mg). MS (ESI): m / z = 690.3 [M+H] + .

[0321] Assay procedure Antibacterial susceptibility test: Determination of 90% growth inhibitory concentration (IC90)

[0322] The in vitro antibacterial activity of the compound was determined according to the following procedure:

[0323] The assay quantitatively measured the in vitro activity of the compound against Acinetobacter baumannii ATCC 17978 or ATCC 17961 using 10-point Iso-Sensitest broth medium.

[0324] Stock compounds in DMSO were serially diluted 2-fold in a 384-well microtiter plate (e.g., in the range of final concentrations 10 - 0.02 μM), seeded with 49 μl of bacterial suspension in Iso-Sensitest medium, and the final cell concentration was ~5x10 (5) CFU / ml in a final volume / well of 50 ul / well. The microtiter plate was incubated at 35 ± 2 °C.

[0325] Bacterial cell growth was determined by measuring the optical density at λ = 600 nm every 20 minutes over a 16 h time course. Growth inhibition was calculated during the logarithmic growth of bacterial cells, and the concentrations that inhibited growth by 50% (IC50) and 90% (IC90) were determined.

[0326] Table 1 provides the 90% growth inhibition concentration (IC90) in micromoles per liter of the compound of the present invention against Acinetobacter baumannii ATCC 17978 or ATCC 17961 strains.

[0327] Certain compounds of the present invention exhibit an IC90 (against Acinetobacter baumannii ATCC 17978 and / or ATCC 17961) of 25 μmol / l or less.

[0328] More specific compounds of the present invention exhibit an IC90 (against Acinetobacter baumannii ATCC 17978 and / or ATCC 17961) of 5 μmol / l or less.

[0329] The most specific compounds of the present invention exhibit an IC90 (against Acinetobacter baumannii ATCC 17978 and / or ATCC 17961) of 1 μmol / l or less.

Table 29-1

Table 29-2

Table 29-3

Table 29-4

Table 29-5

Table 29-6

[0330] Example A The compound of formula (I) can be used as an active ingredient in a manner known per se to produce tablets of the following composition.

[0331] Per tablet Active ingredient 200 mg Microcrystalline cellulose 155 mg Corn starch 25 mg Talc 25 mg Hydroxypropylmethylcellulose 20 mg 425 mg

[0332] Example B The compound of formula (I) can be used as an active ingredient in a known manner to produce capsules of the following composition. Per capsule Active ingredient 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5 mg Magnesium stearate 0.5 mg 220.0 mg

[0333] Example C The compound of formula (I) can be used in a known manner as an active ingredient for the production of an injection solution of the following composition: Active ingredient 100 mg 90% Lactic acid 100 mg Appropriate amount of NaOH or HCl to adjust to pH 4.0 Appropriate amount of sodium chloride or glucose to adjust the osmotic pressure to 290 mOsm / kg Add 100 ml of water for injection (WFI)

[0334] Example D The compound of formula (I) can be used in a known manner as an active ingredient for the production of an injection solution of the following composition: Active ingredient 100 mg Hydroxypropyl-β-cyclodextrin 10 g Appropriate amount of NaOH or HCl to adjust to pH 7.4 Appropriate amount of sodium chloride or glucose to adjust the osmotic pressure to 290 mOsm / kg Add 100 ml of water for injection (WFI)

Claims

1. Compound of formula (I) 【Chemical 1】 wherein R １ In each entity, hydroxy, halogen, cyano, amino, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy, amino-C １ -C ６ -alkoxy-, group 【Chemical 2】 and group C １ -C ６ -alkyl-L ２ is independently selected from; wherein, C １ -C ６ -alkyl is substituted with 1 to 3 substituents selected from hydroxy, amino, halogen, cyano, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl), ２ N-, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkoxy-, carbamoyl, carbamoyl-C １ -C ６ -alkoxy-, carbamimidoyl, (C １ -C ６ -alkyl), ２ N-C １ -C ６ -alkyl-C(O)-NH-C １ -C ６ -alkyl), ２ N-C １ -C ６ -alkyl-C(O)-NH-C １ -C ６ -alkoxy-, C ２ -C ６ -alkynyl-NH-, carboxy and C １ -C ６ -alkoxy and may be substituted; R ２ is independently selected in each occurrence from halogen, cyano, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkyl, and halo-C １ -C ６ -alkoxy; R ３ is selected from hydrogen, C １ -C ６ -alkyl, and halo-C １ -C ６ -alkyl; R ４ is independently selected from halogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, cyano, halo-C １ -C ６ -alkyl, cyano-C １ -C ６ -alkyl, (C １ -C ６ -alkyl) ２ N-, halo-C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)- and 5- to 14-membered heteroaryloxy; R ５ is, in each entity, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, hydroxy-C １ -C ６ -alkyl-, halo-C １ -C ６ -alkyl-, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, oxo, carbamoyl, carbamoyl-C １ -C ６ -alkyl, carboxy, carboxy-C １ -C ６ -alkyl, halogen (fluoro), cyano, C １ -C ６ aminoalkyl-S(O) ２ - and groups [Chemical Formula 3] is independently selected from; R ６ is independently selected from, in each occurrence, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, hydroxy-C １ -C ６ -alkyl-, halo-C １ -C ６ -alkyl-, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, oxo, carbamoyl, carbamoyl-C １ -C ６ -alkyl, carboxy, carboxy-C １ -C ６ -alkyl, halogen, cyano, and C １ -C ６ aminoalkyl-S(O) ２ -; A is a 3- to 14-membered heterocyclyl; B and C are independently selected from 3- to 14-membered heterocyclyl, C ３ -C １０ -cycloalkyl, 5- to 14-membered heteroaryl, and C ６ -C １０ -aryl; L １ and L ３ are independently selected from covalent bonds, -O-, -NH-, -N(C １ -C ６ -alkyl)-, -CH ２ O-, -OCH ２ -, -(CH ２ ) ｓ C(O)-, -CH ２ NH C(O)-, -CH ２ C(O)NH-, -CH ２ -, -NH C(O)-, -S(O) ２ -, -S(O) ２ NH-, -C(O)NH(CH ２ ) ２ -, and -NH-NH C(O)-; L ２ is selected from covalent bonds, carbonyls, -S(O) ２ -, -NHC(O)-, -C(O)NH-, and -S(O) ２ NH-; m is 1, 2, 3, or 4; n is 0, 1, 2, 3, or 4; p is 0, 1, 2, 3, 4, or 5; q is 0, 1, or 2; r is 0 or 1; s is 0, 1, 2, 3, or 4) or a pharmaceutically acceptable salt thereof.

2. wherein m is 1; R １ is amino, amino-C １ -C ６ -alkoxy-, group 【Chemical 4】 and group C １ -C ６ -alkyl-L ２ is selected from; where C １ -C ６ -alkyl is substituted with 1 to 2 substituents selected from hydroxy, amino, cyano, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl) ２ N-, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkoxy-, carbamoyl, carbamoyl-C １ -C ６ -alkoxy-, carbamimidoyl, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-NH-C １ -C ６ -alkoxy-, C ２ -C ６ -alkynyl-NH-, carboxy, and C １ -C ６ -alkoxy and is substituted with 1 to 2 substituents selected therefrom; L １ is selected from -CH ２ O-, -(CH ２ ) ｓ C(O)-, -CH ２ NH C(O)-, -CH ２ C(O)NH-, -CH ２ -, -NH C(O)-, -S(O) ２ -, -S(O) ２ NH-, -C(O)NH(CH ２ ) ２ -, and -NH-NH C(O)-; L ２ is selected from covalent bond, carbonyl, -S(O) ２ -, -NHC(O)-, -C(O)NH-, and -S(O) ２ NH-; q is 0, 1, or 2; s is 0, 1, or 4; B is selected from 3- to 14-membered heterocyclyl, C ３ -C １０ -cycloalkyl, and 5- to 14-membered heteroaryl; R ５ is, in each entity, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, hydroxy-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, oxo, carbamoyl, carbamoyl-C １ -C ６ -alkyl, carboxy, carboxy-C １ -C ６ -alkyl, halogen, aminoalkyl-S(O) ２ -and groups 【Chemical Formula 5】 is independently selected from; where L ３ is a covalent bond or a carbonyl group; r is 0 or 1; C is C ３ -C １０ -cycloalkyl or 3- to 14-membered heterocyclyl; R ６ is hydroxy, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

3. wherein m is 1; R １ is a group [[Chemical Formula 6]] and where L １ is selected from carbonyl, -CH ２ C(O)-, -CH ２ NHC(O)-, and -NHC(O)-; q is 0 or 1; B is a 3- to 14-membered heterocyclyl; R ５ is selected from amino, hydroxy, and hydroxy-C １ -C ６ -alkyl- a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

4. wherein m is 1; R １ is the group 【Chemical Formula 7】 and where L １ is selected from carbonyl, -CH ２ C(O)-, -CH ２ NH C(O)-, and -NH C(O)-; q is 0 or 1; B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexanyl, and piperidyl; R ５ is selected from amino, hydroxy, and hydroxymethyl, a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

5. n is 1, and R ２ is selected from halogen and C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

6. n is 1, and R ２ is selected from chloro and methyl, a compound of formula (I) according to any one of claims 1 to 4 or a pharmaceutically acceptable salt thereof.

7. The compound of formula (I) is a compound of formula (II): [Chemical Formula 8] a compound according to any one of claims 1 to 6 or a pharmaceutically acceptable salt thereof.

8. R ３ is C １ -C ６ -alkyl, a compound of formula (I) according to any one of claims 1 to 7 or a pharmaceutically acceptable salt thereof.

9. R ３ The compound of formula (I) according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof, wherein R is methyl.

10. p is 1, 2, 3, or 4, and R ４ is, in each occurrence, halogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, cyano, halo-C １ -C ６ -alkyl, cyano-C １ -C ６ -alkyl, (C １ -C ６ -alkyl) ２ N-, halo-C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)-, and heteroaryloxy, the compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

11. p is 2 or 3, and R ４ is, in each occurrence, halogen, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy and cyano-C １ -C ６ -alkoxy, independently selected from, a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

12. p is 2 or 3, and R ４ is, in each occurrence, fluoro, chloro, methoxy, FCH ２ O—, F ２ CHO— and CNCH ２ O—, independently selected from, a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

13. The compound of formula (I) is of formula (III) [Chemical Formula 9] wherein R ４ａ is selected from hydrogen, halogen, C １ -C ６ -alkyl, cyano and halo-C １ -C ６ -alkyl: R ４ｂ is selected from hydrogen, halogen, cyano and C １ -C ６ -alkoxy; R ４ｃ is selected from halogen, C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkyl, cyano-C １ -C ６ -alkoxy, (C １ -C ６ -alkyl) ２ N-, halo-C １ -C ６ -alkoxy, C １ -C ６ -alkoxy-C １ -C ６ -alkoxy, (C １ -C ６ -alkyl) ２ N-C(O)- and heteroaryloxy; R ４ｄ is a compound selected from hydrogen and halogen), a compound of formula (I) according to any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof.

14. wherein R ４ａ is a halogen; R ４ｂ is selected from hydrogen and halogen; R ４ｃ is selected from C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkoxy and halo-C １ -C ６ -alkoxy; R ４ｄ is hydrogen, a compound of formula (III) according to claim 13 or a pharmaceutically acceptable salt thereof.

15. wherein R ４ａ is selected from fluoro and chloro; R ４ｂ is selected from hydrogen, fluoro and chloro; R ４ｃ is methoxy, FCH ２ O−, F ２ CHO− and CNCH ２ O−; and is selected from R ４ｄ is hydrogen, a compound of formula (III) according to claim 13 or a pharmaceutically acceptable salt thereof.

16. wherein m is 1; R １ is amino, amino-C １ -C ６ -alkoxy-, group 【Chemical Formula 10】 and group C １ -C ６ -alkyl-L ２ is selected from; where C １ -C ６ -alkyl is substituted with 1 to 2 substituents selected from hydroxy, amino, cyano, C １ -C ６ -alkyl-NH-, (C １ -C ６ -alkyl) ２ N-, amino-C １ -C ６ -alkoxy-C １ -C ６ -alkoxy-, carbamoyl, carbamoyl-C １ -C ６ -alkoxy-, carbamimidoyl, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-NH-C １ -C ６ -alkoxy-, C ２ -C ６ -alkynyl-NH-, carboxy, and C １ -C ６ -alkoxy and is substituted with 1 to 2 substituents selected therefrom; L １ is selected from -CH ２ O-, -(CH ２ 2) ｓ C(O)-, -CH ２ NH C(O)-, -CH ２ C(O)NH-, -CH ２ 2-, -NH C(O)-, -S(O) ２ 2-, -S(O) ２ NH-, -C(O)NH(CH ２ 2) ２ -, and -NH-NH C(O)-; L ２ is selected from covalent bonds, carbonyl, -S(O) ２ -, -NHC(O)-, -C(O)NH-, and -S(O) ２ NH-; q is 0, 1, or 2; s is 0, 1, or 4; B is selected from 3- to 14-membered heterocyclyl, C ３ -C １０ -cycloalkyl, and 5- to 14-membered heteroaryl; R ５ is, in each entity, amino, hydroxy, C １ -C ６ -alkyl, amino-C １ -C ６ -alkyl-, hydroxy-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-, (C １ -C ６ -alkyl) ２ N-C １ -C ６ -alkyl-C(O)-, oxo, carbamoyl, carbamoyl-C １ -C ６ -alkyl, carboxy, carboxy-C １ -C ６ -alkyl, halogen, aminoalkyl-S(O) ２ -and groups 【Chemical 11】 is independently selected from; where L ３ is a covalent bond or a carbonyl group; r is 0 or 1; C is C ３ -C １０ -cycloalkyl or 3- to 14-membered heterocyclyl, and R ６ is hydroxy; n is 1; R ２ is selected from halogen and C １ -C ６ -alkyl; R ３ is C １ -C ６ -alkyl; p is 1, 2, 3, or 4; R ４ is, in each occurrence, independently selected from halogen, C １ -C ６ -alkyl, C １ -C ６ -alkoxy, cyano, halo-C １ -C ６ -alkyl, cyano-C １ -C ６ -alkyl, (C １ -C ６ -alkyl) ２ N-, halo-C １ -C ６ -alkoxy, cyano-C １ -C ６ -alkoxy, C １ [[ID=३४]]-C ６ -alkoxy-C １ -C ６ -alkoxy-, (C １ -C ６ -alkyl) ２ N-C(O)- and heteroaryloxy a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

17. wherein m is 1; R １ is the group 【Chemical Formula 12】 and where L １ is selected from carbonyl, -CH ２ C(O)-, -CH ２ NHC(O)-, and -NHC(O)-; q is 0 or 1; B is a 3- to 14-membered heterocyclyl; R ５ is selected from amino, hydroxy, and hydroxy-C １ -C ６ -alkyl-; n is 1; R ２ is selected from halogen and C １ -C ６ -alkyl; R ３ is C １ -C ６ -alkyl; p is 2 or 3; R ４ is independently selected from halogen, C １ -C ６ -alkoxy, halo-C １ -C ６ -alkoxy and cyano-C １ -C ６ -alkoxy in each occurrence; The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

18. Wherein, m is 1; R １ is a group 【Chemical 13】 and where L １ is selected from carbonyl, -CH ２ C(O)-, -CH ２ NHC(O)-, and -NHC(O)-; q is 0 or 1; B is selected from azetidinyl, pyrrolidinyl, 3-azabicyclo[3.1.0]hexanyl, and piperidyl; R ５ is selected from amino, hydroxy and hydroxymethyl; n is 1, R ２ is selected from chloro and methyl; R ３ is methyl; p is 2 or 3; R ４ is, in each occurrence, independently selected from fluoro, chloro, methoxy, FCH ２ O—, F ２ CHO— and CNCH ２ O—; The compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.

19. The compound of formula (I) is as follows: N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1 - [2 - chloro - 4 - [[5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [2 - (methylamino)ethyl]piperidine - 4 - carboxamide; N - [4 - [4 - [(3R) - 3 - aminopyrrolidine - 1 - carbonyl]piperidine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - (4 - hydroxypiperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [4 - [4 - [2 - (aminomethyl)morpholine - 4 - carbonyl]piperidine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [(3R) - 3 - (hydroxymethyl)piperazine - 1 - carbonyl]piperidine - 1 - carbonyl]phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [2 - (dimethylamino)ethyl]piperazine - 1 - carbonyl]phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [4 - [4 - [(2S,4S) - 4 - aminopyrrolidine - 2 - carbonyl]piperazine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [(2S) - pyrrolidine - 2 - carbonyl]piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [2 - (dimethylamino)acetyl]piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (cyanomethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N-[3-Chloro-4-[4-[(2S)-piperidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-piperidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2R)-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(3-Amino-2-hydroxy-propyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(morpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-N-[3-methyl-4-[4-(morpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-chloro-4-[4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-(1,1-dioxo-1,4-thiazinan-4-carbonyl)piperidine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2R)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(thiomorpholine-4-carbonyl)piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminoazetidine-1-carbonyl)piperidine 1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(aminomethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(5-hydroxypiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-Aminoethyl)-4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carboxamide; N-[3-Chloro-4-(4-piperazin-1-ylsulfonylpiperidine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[[(2S)-pyrrolidine-2-carbonyl]amino]ethyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-2-(aminomethyl)morpholine-4-carbonyl]piperidine-1-carbonyl]-3-methyl-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-piperidylsulfonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-[(2-amino-2-oxo-ethyl)amino]ethyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; (3R)-1-[2-[4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]pyrrolidine-3-carboxylic acid; 1-[2-[4-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazin-1-yl]-2-oxo-ethyl]azetidine-3-carboxylic acid; 5-[3-Chloro-4-(cyanomethoxy)-2-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(3-fluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminocyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-3-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; 5-[2-Chloro-4-(difluoromethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-Hydroxypyrrolidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[4-[4-(2-Aminoacetyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(2S)-Azetidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-Pyrrolidin-1-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-Pyrrolidin-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2R)-Pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3R)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-Pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R)-Pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(Dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-Difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-Pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-(2,3-Difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3S)-Pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-(3-Hydroxypyrrolidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-Difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3-Hydroxyazetidin-3-yl)methyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-Pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-Pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(3-Hydroxyazetidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-Hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-Hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-Hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-Aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(4-Hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(Azetidine-3-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(Pyrrolidin-3-ylmethyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-Difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1 - [2 - Chloro - 4 - [[5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(rac - (1S,5R) - 3 - azabicyclo[3.1.0]hexan - 6 - yl]piperidine - 4 - carboxamide; N - [3 - Chloro - 4 - [4 - (piperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (dimethylamino) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - Chloro - 4 - [4 - (4 - hydroxypiperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3R,4R) - 4 - hydroxypyrrolidin - 3 - yl]piperidine - 4 - carboxamide; 5 - (2 - Chloro - 3 - fluoro - 4 - methoxy - phenyl) - N - [3 - chloro - 4 - [4 - [2 - [(3S) - pyrrolidin - 3 - yl]acetyl]piperazine - 1 - carbonyl]phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - Chloro - 4 - [4 - (piperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 1 - methyl - 5 - (2,3,5 - trifluoro - 4 - methoxy - phenyl)imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(rac - (1S,5R) - 3 - azabicyclo[3.1.0]hexan - 6 - yl]piperidine - 4 - carboxamide; N - [4 - [3 - (2 - aminoethoxy)azetidine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [2 - chloro - 3 - fluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [[(3R) - pyrrolidin - 3 - yl]methyl]piperidine - 4 - carboxamide; 5 - [2 - Chloro - 4 - (difluoromethoxy) - 3 - fluoro - phenyl] - N - [3 - chloro - 4 - [4 - (4 - hydroxypiperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - (4 - hydroxypiperidine - 4 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 5 - (4 - ethoxy - 2,3 - difluoro - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - (5 - hydroxypiperidine - 3 - carbonyl)piperazine - 1 - carbonyl]phenyl] - 5 - [2,3 - difluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carboxamide; 5 - [2 - Chloro - 4 - (difluoromethoxy) - 3 - fluoro - phenyl] - N - [3 - chloro - 4 - [4 - [2 - (4 - hydroxy - 4 - piperidyl)acetyl]piperazine - 1 - carbonyl]phenyl] - 1 - methyl - imidazole - 2 - carboxamide; 5 - [2 - Chloro - 3 - fluoro - 4 - (fluoromethoxy)phenyl] - N - [3 - chloro - 4 - [4 - [2 - (4 - hydroxy - 4 - piperidyl)acetyl]piperazine - 1 - carbonyl]phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [4 - [4 - [1 - (azetidine - 3 - carbonyl)piperidine - 4 - carbonyl]piperazine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [2 - (dimethylamino)acetyl]piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (difluoromethoxy) - 2 - fluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-2-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-(3-hydroxyazetidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-(4-hydroxypiperidine-4-carbonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-3-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R)-pyrrolidin-3-yl]piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-[2-chloro-3-fluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(4-hydroxy-4-piperidyl)acetyl]piperazine-1-carbonyl]phenyl]-5-(4-ethoxy-2,3-difluoro-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[3-(aminomethyl)azetidine-1-carbonyl]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 3-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]propanoic acid; 4-[[1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carbonyl]amino]butanoic acid; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(dimethylcarbamoyl)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(aminomethyl)cyclobutanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-amino-2-oxo-ethyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aR,6aS)-5-(piperidine-4-carbonyl)-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(3-hydroxyazetidin-1-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]azetidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[3-(piperazine-1-carbonyl)azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aR,6aS)-5-[rac-(3R)-pyrrolidine-3-carbonyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[[2-(dimethylamino)acetyl]amino]azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[rac-(3aR,6aS)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-c]pyrrole-5-carbonyl]azetidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[rac-(3aS,6aR)-2-[2-(dimethylamino)acetyl]-1,3,3a,4,6,6a-hexahydropyrrolo[3,4-c]pyrrole-5-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-5-(2,3,4-trifluorophenyl)imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[3-[rac-(3aR,6aR)-2,3,3a,4,6,6a-hexahydro-1H-pyrrolo[3,4-b]pyrrole-5-carbonyl]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3-cyano-2,4-difluoro-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[[2-(dimethylamino)acetyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[3-(prop-2-ynylamino)propyl]piperidine-4-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[4-[3-(dimethylamino)propyl]piperazine-1-carbonyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-Aminoethyl)-1-[[4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]piperidine-4-carboxamide; 1-[[4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-ethyl-benzoyl]-N-[2-[2-(dimethylamino)ethoxy]ethyl]piperidine-4-carboxamide; 5-[4-(Difluoromethoxy)phenyl]-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-4-methoxy-phenyl)-N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]-3-ethyl-phenyl]-5-(3-fluoro-4-isopropoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3-cyclobutyl-1,2,4-oxadiazol-5-yl)methyl]piperidine-1-carbonyl]-3-ethyl-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 4-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(3S,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-(LJ,3-Difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-ethyl-4-hydroxy-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[4-(Cyanomethoxy)-2,3-difluoro-phenyl]-N-[4-[4-[(2S,4S)-4-hydroxy-4-methyl-pyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R,4S)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2,3-Difluoro-4-methoxy-phenyl)-N-[4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3R,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-(piperazine-1-carbonyl)phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(4-guanidinobutanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminopropanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(5-aminopentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(3-cyanopropanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminopropanoylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-yl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[(1S,3R)-3-aminocyclopentanecarbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-aminoethylsulfonylamino)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidyl)piperidine-4-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-pyridylmethyl)piperidine-4-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3R)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[(3S)-pyrrolidine-3-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1 - [2 - Chloro - 4 - [[5 - [2,3 - difluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3S,4R) - 4 - fluoropyrrolidin - 3 - yl]piperidine - 4 - carboxamide; 5 - [3 - Chloro - 2 - fluoro - 4 - (fluoromethoxy)phenyl] - N - [3 - chloro - 4 - [4 - [(2S,4R) - 4 - hydroxypyrrolidine - 2 - carbonyl]piperazine - 1 - carbonyl]phenyl] - 1 - methyl - imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3S,4R) - 4 - fluoropyrrolidin - 3 - yl]piperidine - 4 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [[(3S) - pyrrolidin - 3 - yl]methyl]piperidine - 4 - carboxamide; N - [4 - [4 - (2 - aminoethoxy)piperidine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [4 - [4 - (azetidin - 3 - ylmethoxy)piperidine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [4 - [4 - (4 - aminobutanoyl)piperazine - 1 - carbonyl] - 3 - chloro - phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [3 - chloro - 4 - [4 - [2 - (dimethylamino)acetyl]piperazine - 1 - carbonyl]phenyl] - 5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carboxamide; N - [(2S) - 2 - aminopropyl] - 1 - [2 - chloro - 4 - [[5 - (2,3 - difluoro - 4 - methoxy - phenyl) - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl]piperidine - 4 - carboxamide; N-[4-[4-[1-(2-Aminoethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[1-[2-(dimethylamino)acetyl]piperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(4-Aminopiperidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[2-(difluoromethyl)-3-fluoro-4-methoxy-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(pyrrolidin-3-ylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[[(3R)-pyrrolidin-3-yl]methyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-(4-piperidylsulfonylamino)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[3-(dimethylamino)azetidine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[2-chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-carbamoylpyrrolidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[4-[4-[1-(2-Amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-Aminoethylsulfonyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-(4-methylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(methanesulfonamide)piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-Aminoethylsulfonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(2-oxoimidazolidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(2-Aminoethyl)azetidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2-Pyrrolidin-3-ylacetyl)amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[3-fluoro-4-(fluoromethoxy)-2-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; 5-[3-Chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3S,4S)-3-Amino-4-fluoro-pyrrolidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(4-Pyrrolidin-3-ylsulfonylpiperazine-1-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-Aminobicyclo[1.1.1]pentane-1-carbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[[(1-Methyl-4-piperidyl)amino]carbonyl]piperidine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2-cyano-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(5-oxopyrrolidin-3-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-(dimethylamino)propanoylamino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[2-Chloro-4-(cyanomethoxy)-3-fluoro-phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-[3-Chloro-4-(cyanomethoxy)phenyl]-N-[3-chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-(4-piperidylmethyl)piperidine-4-carboxamide; N-[4-[4-[3-(aminomethyl)azetidine-1-carbonyl]piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(methylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-aminoazetidine-1-carbonyl)piperidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]amino]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-[2-(2-aminoethoxy)ethoxy]propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(5-oxopyrrolidin-2-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(5-oxopyrrolidine-2-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-(4-aminopiperidine-1-carbonyl)-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(methylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(6-oxopiperidine-3-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(2-azaspiro[3.3]heptane-6-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-5-(2-chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-[(2R,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[6-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]-2-azaspiro[3.3]heptane-2-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[3-[2-[[2-(dimethylamino)acetyl]amino]ethoxy]propanoyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-1-methyl-N-[3-methyl-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]imidazole-2-carboxamide; N-[3-Chloro-4-[3-[[rac-(3R)-pyrrolidine-3-carbonyl]amino]pyrrolidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-(2,6-diazaspiro[3.3]heptane-2-carbonyl)phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[(1S)-2-Amino-1-methyl-ethyl]-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[1-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]pyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(3S)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[2-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]-2,6-diazaspiro[3.3]heptane-6-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(2-fluoro-3,4-dimethoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[5-[(3aS,4S,6aR)-2-oxo-1,3,3a,4,6,6a-hexahydrothieno[3,4-d]imidazol-4-yl]pentanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(2,5-dioxoimidazolidin-4-yl)acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[3-(2-aminoethoxy)propanoylamino]pyrrolidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 2-[4-[4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperazine-1-carbonyl]-1-piperidyl]acetic acid; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-methoxyethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(2-pyridyloxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(4-pyridyloxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-(3,4-difluoro-5-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[2-(dimethylamino)ethyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-pyrimidin-2-yloxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethyl)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-(azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[3-chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(2-aminoethoxy)propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[1-(2-amino-2-oxo-ethyl)piperidine-4-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[(3R)-3-aminopyrrolidine-1-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; 1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S)-pyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[2-(dimethylamino)acetyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[2-fluoro-4-(fluoromethoxy)phenyl-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[2,3-difluoro-4-(fluoromethoxy)phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-(2-aminoethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; 1 - [2 - Chloro - 4 - [[5 - [2,3 - difluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - (4 - piperidyl)piperidine - 4 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3R) - pyrrolidin - 3 - yl]piperidine - 4 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - (4 - piperidyl)piperidine - 4 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3S,4S) - 4 - hydroxypyrrolidin - 3 - yl]piperidine - 4 - carboxamide; N - [3 - Chloro - 4 - [4 - [2 - (4 - hydroxy - 4 - piperidyl)acetyl]piperazine - 1 - carbonyl]phenyl] - 5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [4 - (difluoromethoxy) - 2,3 - difluoro - phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3R,4R) - 4 - hydroxypyrrolidin - 3 - yl]piperidine - 4 - carboxamide; N - [3 - Chloro - 4 - [4 - [2 - (dimethylamino)acetyl]piperazine - 1 - carbonyl]phenyl] - 5 - [2 - fluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carboxamide; 1 - [2 - Chloro - 4 - [[5 - [2,3 - difluoro - 4 - (fluoromethoxy)phenyl] - 1 - methyl - imidazole - 2 - carbonyl]amino]benzoyl] - N - [(3R) - pyrrolidin - 3 - yl]piperidine - 4 - carboxamide; N-[4-[3-[[3-(aminomethyl)cyclobutanecarbonyl]amino]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[3-[(2-aminoacetyl)amino]azetidine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-(3-carbamoylcyclobutanecarbonyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-hydroxycyclobutanecarbonyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-(3-methoxypropanoyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[3-(3-amino-3-oxo-propoxy)propanoyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; and N-[4-[4-(5-amino-5-oxo-pentanoyl)piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide The compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

20. The compound of formula (I) is as follows: N-[3-chloro-4-[4-[rac-(1R,5S)-3-azabicyclo[3.1.0]hexane-6-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[3-Chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[3-chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-(2-pyrrolidin-3-ylacetyl)piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; 4-[2-Chloro-4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; 1-[2-Chloro-4-[[5-[4-(difluoromethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[2-[(3S)-Pyrrolidin-3-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 5-[3-Chloro-2-fluoro-4-(fluoromethoxy)phenyl]-N-[4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4S)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,3S)-3-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-Chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-Chloro-4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-(piperidine-4-carbonyl)piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[4-[4-[2-(azetidin-3-yl)acetyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(difluoromethoxy)-2-fluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-chloro-4-[4-[2-[(2S)-pyrrolidin-2-yl]acetyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carboxamide; N-[3-chloro-4-[4-[(3R)-3-(hydroxymethyl)piperazine-1-carbonyl]piperidine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3R,4R)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[4-[4-[(2S,4S)-4-aminopyrrolidine-2-carbonyl]piperazine-1-carbonyl]-3-chloro-phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; 4-[2-chloro-4-[[5-(2,3-difluoro-4-methoxyphenyl)-1-methyl-imidazole-2-carbonyl]amino]benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; N-[3-chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-(Azetidin-3-ylmethyl)-1-[2-chloro-4-[[5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carbonyl]amino]benzoyl]piperidine-4-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-[4-(cyanomethoxy)-2,3-difluoro-phenyl]-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(2S,4R)-4-hydroxypyrrolidine-2-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; N-[3-Chloro-4-[4-[(3S,4R)-3-hydroxypiperidine-4-carbonyl]piperazine-1-carbonyl]phenyl]-5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carboxamide; 4-[4-[[5-(2,3-difluoro-4-methoxy-phenyl)-1-methyl-imidazole-2-carbonyl]amino]-2-methyl-benzoyl]-N-[(3S,4S)-4-hydroxypyrrolidin-3-yl]piperazine-1-carboxamide; and 5-(2-Chloro-3-fluoro-4-methoxy-phenyl)-N-[4-[4-(4-hydroxypiperidine-4-carbonyl)piperazine-1-carbonyl]-3-methyl-phenyl]-1-methyl-imidazole-2-carboxamide A compound of formula (I) according to claim 1, or a pharmaceutically acceptable salt thereof, selected from

21. A process for preparing a compound of formula (I) according to any one of claims 1 to 20, Scheme 1 【Chemical 14】 (wherein Ra is alkyl and R2, R3 and n are as defined in any one of claims 1 to 20); Scheme 2 【Chemical Formula 15】 (wherein Ra is alkyl, "Component X" is a cyclic amine with or without PG, "PG" means a suitable protecting group, and wherein R4 and p are as defined in any one of claims 1 to 20); and Scheme 3 【Chemical 16】 (Here, X is a cyclic amine with or without PG, "PG" means an appropriate protecting group, where component Q is an amine with or without PG, "PG" means an appropriate protecting group, where component Y-Q of Route 2 is an acid (Y)-amine (Q) compound with or without PG, "PG" means an appropriate protecting group, and where component X-Y-Q of Route 3 is an alkyl halide (Y) bonded to two amines (X-cyclic amine and Q) with or without PG, "PG" means an appropriate protecting group) A method comprising.

22. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as a therapeutic active substance.

23. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, and a therapeutically inert carrier.

24. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use as an antibiotic.

25. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of nosocomial infections and diseases caused thereby.

26. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Gram-negative bacteria and diseases caused thereby.

27. The pharmaceutical composition according to claim 26, wherein the Gram-negative bacteria are selected from Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species, and Escherichia coli.

28. The pharmaceutical composition according to claim 27, wherein the Gram-negative bacteria are Acinetobacter baumannii.

29. A pharmaceutical composition comprising the compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for use in the treatment or prevention of infections caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and diseases caused thereby. **Claim 30** A method for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, in a non-human mammal, and a disease resulting therefrom, the method comprising administering to the non-human mammal a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof. **Claim 31** Use of a compound of formula (I) according to any one of claims 1 to 20, or a pharmaceutically acceptable salt thereof, for the preparation of a medicament useful for the treatment or prevention of an infectious disease caused by Enterococcus faecium, Staphylococcus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Enterobacter species or Escherichia coli, or a combination thereof, and a disease resulting therefrom.

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